Delivery of highly lipophilic agents via medical devices

ABSTRACT

An apparatus and system for delivering a lipophilic agent associated with a medical device including: a medical device, a first lipophilic agent capable of penetrating a body lumen, wherein the transfer coefficients of the first lipophilic agent is by an amount that is statistically significant of at least approximately 5,000, wherein the first lipophilic agent is associated with the medical device, wherein the first lipophilic agent/medical device is placed adjacent to said body lumen, and wherein a therapeutically effective amount of the first lipophilic agent is delivered to a desired area within a subject. Furthermore, the invention relates to a method for improving patency in a subject involving placement of a medical device in a body lumen for treating and/or preventing adjacent diseases or maintaining patency of the body lumen.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. Ser. No. 10/796,243filed Mar. 9, 2004 now U.S. Pat. No. 7,445,792, which claims priority toU.S. Ser. No. 60/453,555 filed Mar. 10, 2003 and this application is acontinuation-in-part of U.S. Ser. No. 10/977,288 filed Oct. 29, 2004 nowU.S. Pat. No. 7,399,480, which is a continuation-in-part of U.S. Ser.No. 10/235,572, filed Sep. 6, 2002 now abandoned, which is acontinuation in part of U.S. Ser. No. 09/950,307, filed Sep. 10, 2001,now U.S. Pat. No. 6,890,546, which is a continuation-in-part of U.S.Ser. No. 09/433,001, filed Nov. 2, 1999, now U.S. Pat. No. 6,329,386,which is a divisional of U.S. Ser. No. 09/159,945, filed Sep. 24, 1998,now U.S. Pat. No. 6,015,815 and claims priority to U.S. Ser. No.60/060,015, filed Sep. 26, 1997; this application also claims priorityto U.S. Ser. No. 60/664,328 filed on Mar. 23, 2005, U.S. Ser. No.60/727,080 filed Oct. 14, 2005, U.S. Ser. No. 60/726,878 filed Oct. 14,2005, U.S. Ser. No. 60/732,577 filed Oct. 17, 2005, and U.S. Ser. No.60/727,196 filed Oct. 14, 2005; the entirety of all the above of whichis incorporated herein by reference.

FIELD OF THE INVENTION

The invention relates to apparatuses, systems, and methods of remotedrug delivery of highly lipophilic agents utilizing medical devices, andmore specifically, lipophilic agents having a transfer coefficient of atleast approximately 5,000 (ug/mL)⁻¹.

BACKGROUND OF THE INVENTION

The compound cyclosporine (cyclosporin A) has found wide use since itsintroduction in the fields of organ transplantation andimmunomodulation, and has brought about a significant increase in thesuccess rate for transplantation procedures. Recently, several classesof macrocyclic compounds having potent immunomodulatory activity havebeen discovered. Okuhara et al., in European Patent Application No.184,162, published Jun. 11, 1986, disclose a number of macrocycliccompounds isolated from the genus Streptomyces, including theimmunosuppressant FK-506, a 23-membered macrocyclic lactone, which wasisolated from a strain of S. tsukubaensis.

Other related natural products, such as FR-900520 and FR-900523, whichdiffer from FK-506 in their alkyl substituent at C-21, have beenisolated from S. hygroscopicus yakushimnaensis. Another analog,FR-900525, produced by S. tsukubaensis, differs from FK-506 in thereplacement of a pipecolic acid moiety with a proline group.Unsatisfactory side-effects associated with cyclosporine and FK-506 suchas nephrotoxicity, have led to a continued search for immunosuppressantcompounds having improved efficacy and safety, including animmunosuppressive agent which is effective topically, but ineffectivesystemically (U.S. Pat. No. 5,457,111).

Rapamycin is a macrocyclic triene antibiotic produced by Streptomyceshygroscopicus, which was found to have antifungal activity, particularlyagainst Candida albicans, both in vitro and in vivo (C. Vezina et al.,J. Antibiot. 1975, 28, 721; S. N. Sehgal et al., J. Antibiot. 1975, 28,727; H. A. Baker et al., J. Antibiot. 1978, 31, 539; U.S. Pat. No.3,929,992; and U.S. Pat. No. 3,993,749).

Rapamycin alone (U.S. Pat. No. 4,885,171) or in combination withpicibanil (U.S. Pat. No. 4,401,653) has been shown to have antitumoractivity. In 1977, rapamycin was also shown to be effective as animmunosuppressant in the experimental allergic encephalomyelitis model,a model for multiple sclerosis; in the adjuvant arthritis model, a modelfor rheumatoid arthritis; and was shown to effectively inhibit theformation of IgE-like antibodies (R. Martel et al., Can. J. Physiol.Pharmacol., 1977, 55, 48).

The immunosuppressive effects of rapamycin have also been disclosed inFASEB, 1989, 3, 3411 as has its ability to prolong survival time oforgan grafts in histoincompatible rodents (R. Morris, Med. Sci. Res.,1989, 17, 877). The ability of rapamycin to inhibit T-cell activationwas disclosed by M. Strauch (FASEB, 1989, 3, 3411). These and otherbiological effects of rapamycin are reviewed in Transplantation Reviews,1992, 6, 39-87.

Rapamycin has been shown to reduce neointimal proliferation in animalmodels, and to reduce the rate of restenosis in humans. Evidence hasbeen published showing that rapamycin also exhibits an anti-inflammatoryeffect, a characteristic which supported its selection as an agent forthe treatment of rheumatoid arthritis. Because both cell proliferationand inflammation are thought to be causative factors in the formation ofrestenotic lesions after balloon angioplasty and stent placement,rapamycin and analogs thereof have been proposed for the prevention ofrestenosis.

Ester and diester derivatives of rapamycin (esterification at positions31 and 42) have been shown to be useful as antifungal agents (U.S. Pat.No. 4,316,885) and as water soluble prodrugs of rapamycin (U.S. Pat. No.4,650,803).

Fermentation and purification of rapamycin and 30-demethoxy rapamycinhave been described in the literature (C. Vezina et al. J. Antibiot.(Tokyo), 1975, 28 (10), 721; S. N. Sehgal et al., J. Antibiot. (Tokyo),1975, 28(10), 727; 1983, 36(4), 351; N. L. Pavia et al., J. NaturalProducts, 1991, 54(1), 167-177).

Numerous chemical modifications of rapamycin have been attempted. Theseinclude the preparation of ester and diester derivatives of rapamycin(WO 92/05179), 27-oximes of rapamycin (EP0 467606); 42-oxo analog ofrapamycin (U.S. Pat. No. 5,023,262); bicyclic rapamycins (U.S. Pat. No.5,120,725); rapamycin dimers (U.S. Pat. No. 5,120,727); silyl ethers ofrapamycin (U.S. Pat. No. 5,120,842); and arylsulfonates and sulfamates(U.S. Pat. No. 5,177,203). Rapamycin was recently synthesized in itsnaturally occurring enantiomeric form (K. C. Nicolaou et al., J. Am.Chem. Soc., 1993, 115, 4419-4420; S. L. Schreiber, J. Am. Chem. Soc.,1993, 115, 7906-7907; S. J. Danishefsky, J. Am. Chem. Soc., 1993, 115,9345-9346.

It has been known that rapamycin, like FK-506, binds to FKBP-12(Siekierka, J. J.; Hung, S. H. Y.; Poe, M.; Lin, C. S.; Sigal, N. H.Nature, 1989, 341, 755-757; Harding, M. W.; Galat, A.; Uehling, D. E.;Schreiber, S. L. Nature 1989, 341, 758-760; Dumont, F. J.; Melino, M.R.; Staruch, M. J.; Koprak, S. L.; Fischer, P. A.; Sigal, N. H. J.Immunol. 1990, 144, 1418-1424; Bierer, B. E.; Schreiber, S. L.;Burakoff, S. J. Eur. J. Immunol. 1991, 21, 439-445; Fretz, H.; Albers,M. W.; Galat, A.; Standaert, R. F.; Lane, W. S.; Burakoff, S. J.;Bierer, B. E.; Schreiber, S. L. J. Am. Chem. Soc. 1991, 113, 1409-1411).Recently it has been discovered that the rapamycin/FKBP-12 complex bindsto yet another protein, which is distinct from calcineurin, the proteinthat the FK-506/FKBP-12 complex inhibits (Brown, E. J.; Albers, M. W.;Shin, T. B.; Ichikawa, K.; Keith, C. T.; Lane, W. S.; Schreiber, S. L.Nature 1994, 369, 756-758; Sabatini, D. M.; Erdjument-Bromage, H.; Lui,M.; Tempest, P.; Snyder, S. H. Cell, 1994, 78, 35-43).

Percutaneous transluminal coronary angioplasty (PTCA) was developed byAndreas Gruntzig in the 1970's. The first canine coronary dilation wasperformed on Sep. 24, 1975; studies showing the use of PTCA werepresented at the annual meetings of the American Heart Association thefollowing year. Shortly thereafter, the first human patient was studiedin Zurich, Switzerland, followed by the first American human patients inSan Francisco and New York. While this procedure changed the practice ofinterventional cardiology with respect to treatment of patients withobstructive coronary artery disease, the procedure did not providelong-term solutions. Patients received only temporary abatement of thechest pain associated with vascular occlusion; repeat procedures wereoften necessary. It was determined that the existence of restenoticlesions severely limited the usefulness of the new procedure. In thelate 1980's, stents were introduced to maintain vessel patency afterangioplasty. Stenting is involved in 90% of angioplasty performed today.Before the introduction of stents, the rate of restenosis ranged from30% to 50% of the patients who were treated with balloon angioplasty.The recurrence rate after dilatation of in-stent restenosis may be ashigh as 70% in selected patient subsets, while the angiographicrestenosis rate in de novo stent placement is about 20%. Placement ofthe stent reduced the restenosis rate to 15% to 20%. This percentagelikely represents the best results obtainable with purely mechanicalstenting. The restenotic lesion is caused primarily by neointimalhyperplasia, which is distinctly different from atherosclerotic diseaseboth in time-course and in histopathologic appearance. Restenosis is ahealing process of damaged coronary arterial walls, with neointimaltissue impinging significantly on the vessel lumen. Vascularbrachytherapy appears to be efficacious against in-stent restenoticlesions. Radiation, however, has limitations of practicality andexpense, and lingering questions about safety and durability.

Accordingly, it is desired to reduce the rate of restenosis by at least50% of its current level. It is for this reason that a major effort isunderway by the interventional device community to fabricate andevaluate drug-eluting stents. Such devices could have many advantages ifthey were successful, principally since such systems would need noauxiliary therapies, either in the form of periprocedural techniques orchronic oral pharmacotherapy.

In surgical or other related invasive medicinal procedures, theinsertion of a medical device having an interventional componentincluding stent devices in blood vessels, urinary tracts or otherdifficult to access places for the purpose of preventing restenosis,providing vessel or lumen wall support or reinforcement and for othertherapeutic or restorative functions has become a common form oflong-term treatment. Typically, such interventional components areapplied to a location of interest utilizing a vascular catheter, orsimilar transluminal device, to carry the stent to the location ofinterest where it is thereafter released to expand or be expanded insitu. These devices are generally designed as permanent implants whichmay become incorporated in the vascular or other tissue that theycontact at implantation.

Implanted interventional components including stents have also been usedto carry medicinal agents, such as thrombolytic agents. U.S. Pat. No.5,163,952 to Froix discloses a thermal memoried expanding plastic stentdevice that can be formulated to carry a medicinal agent by utilizingthe material of the stent itself as an inert polymeric drug carrier.Drug elution rates from a drug-loaded coating containing a hydrophilic(or lipophobic) drug are usually very fast initially when the coateddevice contacts body fluid or blood. Thus, an ongoing problem for drugdelivery stents is achieving therapeutic drug concentrations at a targetsite within the body with minimal losses and systemic side effects. Onetechnique to reduce the so-called burst effect is to add a membranecontaining porosigen over the coating layer containing the biologicallyactive material, as described for example in U.S. Pat. Nos. 5,605,696and 5,447,724. Polymers are also used on stents as drug releasecoatings, as taught for example in U.S. Pat. No. 6,419,692. U.S. Pat.No. 6,284,305 describes elastomer coated implants in which the elastomerovercoat to control release of biologically active agent from anundercoat applied to a stent. U.S. Pat. No. 5,624,411 discloses a porouspolymer on a stent to control the administration of a drug. WO 0187372describes a stent coated with a polymer loaded with a combination ofdrugs, including rapamycin and dexamethasone. Pinchuk, in U.S. Pat. No.5,092,877, discloses a stent of a polymeric material that may beemployed with a coating associated with the delivery of drugs. Otherpatents which are directed to devices of the class utilizingbiodegradable or biosorbable polymers include Tang et al, U.S. Pat. No.4,916,193 and MacGregor, U.S. Pat. No. 4,994,071. Sahatjian in U.S. Pat.No. 5,304,121, discloses a coating applied to a stent consisting of ahydrogel polymer and a preselected drug; possible drugs include cellgrowth inhibitors and heparin. A further method of making a coatedintravascular stent carrying a therapeutic material in which a polymercoating is dissolved in a solvent and the therapeutic material dispersedin the solvent and the solvent thereafter evaporated is described inBerg et al, U.S. Pat. No. 5,464,650.

An article by Michael N. Helmus entitled “Medical Device Design—ASystems Approach: Central Venous Catheters”, 22nd International Societyfor the Advancement of Material and Process Engineering TechnicalConference (1990) relates to polymer/drug/membrane systems for releasingheparin. Those polymer/drug/membrane systems require two distinct layersto function. Ding et al., U.S. Pat. No. 6,358,556 described a processfor coating a stent prosthesis using a biostable hydrophobic elastomerin which biologically active species are incorporated within a curedcoating. In these coatings, the amount of polymer is relatively high,for example about 70% of the drug-loaded coating.

Thus, there remains a need for improved controlled delivery of ahydrophilic beneficial agent from a medical device, wherein the medicaldevice reduces the burst effect and allows prolonged delivery of thebeneficial agent without the side effects associated with somehydrophobic coatings. Also, there exists a need for a medical devicewith improved control of local release of two or more beneficial agents.Further, a need exists for a medical device that is capable of releasinga beneficial agent or agents immediately or soon after delivery followedby the controlled delivery of the same or other beneficial agents overprolonged time periods.

Previous drug eluting stents have been constructed to delivertherapeutic agents predominantly to the tissue immediately adjacent tothe site of stent placement. The objective has been to controlneointimal formation and allow the coronary vascular system to achieverapid healing. Consequently, the bulk of the drug or drugs delivered iseither present in the vascular tissue adjacent to the site of stentimplantation, stays on the stent for prolonged periods, or is releasedinto the blood stream. There is an unmet need for agents and deviceswhich offer deep penetration of beneficial agents to tissues notimmediately adjacent to the device. For example, delivery of a drug froma stent which not only delivers drug to the adjacent tissue, but alsopenetrates the myocardium and provides therapeutically useful doses ofdrug to a wide volume of tissue is particularly attractive.

SUMMARY OF THE INVENTION

The invention relates to a system for delivering a lipophilic agentincluding: a medical device, a first lipophilic agent capable ofpenetrating a body lumen, wherein the transfer coefficient of the firstlipophilic agent is by an amount of at least approximately 5,000(ug/mL)⁻¹, wherein the first lipophilic agent is associated with themedical device, wherein the first lipophilic agent/medical device isplaced adjacent to said body lumen, and wherein a therapeuticallyeffective amount of the first lipophilic agent is delivered to a desiredarea within a subject.

Another aspect of the invention relates to a method for improvingpatency in a subject involving placement of a medical device in a bodylumen for treating and/or preventing adjacent diseases or maintainingpatency of the body lumen including: providing a medical device in abody lumen, providing a first lipophilic agent capable of penetrating abody lumen, wherein the transfer coefficient of the first lipophilicagent is by an amount of at least approximately 5,000 (ug/mL)⁻¹, whereinthe first lipophilic agent is associated with the medical device,placing the first lipophilic agent/medical device adjacent to a bodylumen, and delivering a therapeutically effective amount of the firstlipophilic agent to a desired area within a subject.

Yet another aspect of the invention relates to a medical deviceincluding: a therapeutically effective amount of a first lipophilicagent associated with the medical device, wherein the first lipophilicagent is capable of penetrating a body lumen, wherein the transfercoefficient of the first lipophilic agent is by an amount of at leastapproximately 5,000 (ug/mL)⁻¹, and wherein the first lipophilicagent/medical device is capable of being placed adjacent to a body lumenof a subjects and deliver a therapeutically effective amount of thefirst lipophilic agent to a desired area in a subject.

Still yet another aspect of the invention relates to a stent including:a therapeutically effective amount of a first lipophilic agentassociated with the stent, wherein the first lipophilic agent is capableof penetrating a body lumen, wherein the transfer coefficient of thefirst lipophilic agent is by an amount of at least approximately 5,000(ug/mL)⁻¹, and wherein the first lipophilic agent/stent is capable ofbeing placed adjacent to a body lumen of a subject and deliver atherapeutically effective amount of the first lipophilic agent to adesired area in a subject.

An object of embodiments of the invention is to provide increased uptakeof a drug into the vessel wall with minimal loss of the drug to the morehydrophilic systemic circulation.

A further object of embodiments of the invention is to provide a drugdelivery system that reduces restenosis in percutaneous intervention ofcoronary arteries.

Other objects of the invention provide a better understanding of the invivo pharmacokinetics of drug-eluting medical devices (includingDES—drug-eluting stents).

Yet other object of embodiments of the invention is to provide a morehighly lipophilic compound than rapamycin.

Still yet other objects of embodiments of the invention are to improvedrug transport into tissue cells of the arterial wall and improve tissueretention of the drug.

Yet another object of embodiments of the invention is to provide adeeper penetration and wider distribution of the drug from the medicaldevice to the adjacent tissue allowing therapeutically effect amounts ofthe drug to the targeted area in a subject.

It is to be understood that the foregoing general description and thefollowing detailed description are exemplary and explanatory only andare not to be viewed as being restrictive of the invention as claimed.Further advantages of this invention will be apparent after a review ofthe following detailed description of the disclosed embodiments whichare illustrated schematically in the accompanying drawings and in theappended claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a side view of an exemplary interventional device (stent),according to embodiments of the invention.

FIG. 2 is a side view in elevation showing a PC-coated(phosphorylcholine-coated) stent suitable for use in this invention,according to embodiments of the invention.

FIG. 3A is a cross-sectional view of a vessel segment in which wasplaced a stent coated with a polymer only, according to embodiments ofthe invention.

FIG. 3B is a cross-sectional view of a vessel segment in which wasplaced a stent coated with a polymer plus drug, according to embodimentsof the invention.

FIG. 4 is a cross-sectional view of a stent strut having a layer of abeneficial agent and hydration inhibitor in mixture, according toembodiments of the invention.

FIG. 5 is a cross-sectional view of a stent strut having a first layerof a beneficial agent and a second layer of a second beneficial agentacting as a hydration inhibitor, according to embodiments of theinvention.

FIG. 6 is a cross-sectional view of a stent strut having a base layer ofpolymer material which is loaded with a mixture of a beneficial agentand a hydration inhibitor, according to embodiments of the invention.

FIG. 7 is a cross-sectional view of a stent strut having a base layer ofa polymer material which is loaded with a beneficial agent and a secondlayer of a second beneficial agent acting as a hydration inhibitor,according to embodiments of the invention.

FIG. 8 is a cross sectional view of a stent strut having layers of afirst beneficial agent alternating with layers of a second beneficialagent/hydration inhibitor, according to embodiments of the invention.

FIG. 9A is a top view of a drug-loaded coupon, according to embodimentsof the invention.

FIG. 9B is a side view of a drug-loaded coupon according to embodimentsof the invention.

FIG. 10 is a graph showing the six-hour elution profile of thebeneficial agent fenofibrate and the hydration inhibitor zotarolimus(ABT-578), according to embodiments of the invention.

FIG. 11 is a graph showing the six-hour elution profile of beneficialagent ABT-627 (atrasentan) in the presence of hydration inhibitorzotarolimus, according to embodiments of the invention.

FIG. 12 is a graph showing the six-hour elution profile of beneficialagent dipyridamole in the presence of hydration inhibitor zotarolimus,according to embodiments of the invention.

FIG. 13 is a graph showing the six hour elution profiles of beneficialagent dexamethasone in the presence of hydration inhibitor zotarolimus,according to embodiments of the invention.

FIG. 14 is a graph showing the six-hour elution profile of beneficialagent dexamethasone in the presence of hydration inhibitor zotarolimuson a PC-coated stent, according to embodiments of the invention.

FIG. 15 is a graph showing the accelerated elution profiles ofbeneficial agent dexamethasone in the presence of hydration inhibitorzotarolimus at different zotarolimus-to-dexamethasone ratios, accordingto embodiments of the invention.

FIG. 16 shows the overlay of a chromatogram from a stent loaded withonly dexamethasone and a chromatogram from a stent loaded with bothdexamethasone and zotarolimus at a 1-to-1 ratio, according toembodiments of the invention.

FIG. 17 shows blood concentrations±SEM (n=3) of tetrazole-containingrapamycin analogs dosed in monkeys, according to embodiments of theinvention.

FIG. 18 is a side view in elevation showing a stent suitable for use inthis invention, according to embodiments of the invention.

FIG. 19A is a cross-sectional view of a vessel segment in which wasplaced a stent coated with a polymer only, according to embodiments ofthe invention.

FIG. 19B is a cross-sectional view of a vessel segment in which wasplaced a stent coated with a polymer plus drug, according to embodimentsof the invention.

FIG. 20 is a graph illustrating the partition coefficients andsolubilities of various drugs utilized in drug-eluting devices,according to embodiments of the invention.

FIG. 21 is a graph illustrating the transfer coefficients for variousdrugs utilized in drug-eluting devices, according to embodiments of theinvention.

FIG. 22 is a graph illustrating the amount of drug concentration(ZoMaxx™ stent vs Cypher® stent) in rabbit tissue over 28 days,according to embodiments of the invention.

FIG. 23 is a graph illustrating the amount of drug concentration(ZoMaxx™ stent vs Cypher® stent) in rabbit blood over 28 days, accordingto embodiments of the invention.

FIG. 24 is a graph illustrating the LogP values of various drugcompounds, according to embodiments of the invention.

FIG. 25 is a graph illustrating the results of experiments performed inpigs utilizing zotarolimus, graph shows the blood, liver, kidney,artery, and myocardial concentrations of zotarolimus, according toembodiments of the invention.

DETAILED DESCRIPTION OF EMBODIMENTS OF THE INVENTION

The invention relates to apparatuses, methods, and drug delivery systemsfor delivering a lipophilic agent to a body lumen. One aspect of theinvention relates to a system for delivering a lipophilic agentincluding: a medical device, a first lipophilic agent capable ofpenetrating a body lumen, wherein the transfer coefficient of the firstlipophilic agent is by an amount of at least approximately 5,000(ug/mL)⁻¹, wherein the first lipophilic agent is associated with themedical device, wherein the first lipophilic agent/medical device isplaced adjacent to said body lumen, and wherein a therapeuticallyeffective amount of the first lipophilic agent is delivered to a desiredarea within a subject.

Another aspect of the invention relates to a method for improvingpatency in a subject involving placement of a medical device in a bodylumen for treating and/or preventing adjacent diseases or maintainingpatency of the body lumen including: providing a medical device in abody lumen, providing a first lipophilic agent capable of penetrating abody lumen, wherein the transfer coefficient of the first lipophilicagent is by an amount of at least approximately 5,000 (ug/mL)⁻¹, whereinthe first lipophilic agent is associated with the medical device,placing the first lipophilic agent/medical device adjacent to a bodylumen, and delivering a therapeutically effective amount of the firstlipophilic agent to a desired area within a subject.

Yet another aspect of the invention relates to a medical deviceincluding: a therapeutically effective amount of a first lipophilicagent associated with the medical device, wherein the first lipophilicagent is capable of penetrating a body lumen, wherein the transfercoefficient of the first lipophilic agent is by an amount of at leastapproximately 5,000 (ug/mL)⁻¹, and wherein the first lipophilicagent/medical device is capable of being placed adjacent to a body lumenof a subject and deliver a therapeutically effective amount of the firstlipophilic agent to a desired area in a subject.

Still yet another aspect of the invention relates to a stent including:a therapeutically effective amount of a first lipophilic agentassociated with the stent, wherein the first lipophilic agent is capableof penetrating a body lumen, wherein the transfer coefficient of thefirst lipophilic agent is by an amount of at least approximately 5,000(ug/mL)⁻¹, and wherein the first lipophilic agent/stent is capable ofbeing placed adjacent to a body lumen of a subject and deliver atherapeutically effective amount of the first lipophilic agent to adesired area in a subject.

Definitions

It is noted that, as used in this specification and the appended claims,the singular forms “a,” “an,” and “the” include plural referents unlessexpressly and unequivocally limited to one referent. The term “agent” asused herein is synonymous with “at least one agent,” “compound,” or “atleast one compound,” and means at least one drug or codrug, or a prodrugthereof.

The term “beneficial agent,” used herein, means agents that exert atherapeutically beneficial effect when delivered from suitable medicaldevices. “Beneficial agent” as used herein, refers to any compound,mixture of compounds, or composition of matter consisting of a compound,which produces a beneficial or useful result. The beneficial agent canbe a polymer, a marker, such as a radiopaque dye or particles, or can bea drug, including pharmaceutical and therapeutic agents, or an agentincluding inorganic or organic drugs without limitation. The agent ordrug can be in various forms such as uncharged molecules, components ofmolecular complexes, pharmacologically-acceptable salts such ashydrochloride, hydrobromide, sulfate, laurate, palmitate, phosphate,nitrate, borate, acetate, maleate, tartrate, oleate, and salicylate.

An agent or drug that is water insoluble can be used in a form that is awater-soluble derivative thereof to effectively serve as a solute, andon its release from the device, is converted by enzymes, hydrolyzed bybody pH, or metabolic processes to a biologically active form.Additionally, the agents or drug formulations can have various knownforms such as solutions, dispersions, pastes, particles, granules,emulsions, suspensions and powders. The drug or agent may or may not bemixed with polymer or a solvent as desired.

For purposes of illustration and not limitation, the drug or agent caninclude antithrombotics, anticoagulants, antiplatelet agents,thrombolytics, antiproliferatives, anti-inflammatories, agents thatinhibit hyperplasia, inhibitors of smooth muscle proliferation,antibiotics, growth factor inhibitors, or cell adhesion inhibitors.Other drugs or agents include but are not limited to antineoplastics,antimitotics, antifibrins, antioxidants, agents that promote endothelialcell recovery, antiallergic substances, radiopaque agents, viralvectors, antisense compounds, oligionucleotides, cell permeationenhancers, cell adhesion promoters, nucleic acids, monoclonalantibodies, hypogylycemic agents, hypolipidemic agents, proteins, agentsuseful for erythropoiesis stimulation, angiogenesis agents, andcombinations thereof.

Examples of such antithrombotics, anticoagulants, antiplatelet agents,and thrombolytics include sodium heparin, low molecular weight heparins,heparinoids, hirudin, argatroban, forskolin, vapriprost, prostacyclinand prostacylin analogues, dextran, D-phe-pro-arg-chloromethylketone(synthetic antithrombin), dipyridamole, glycoprotein IIb/IIIa (plateletmembrane receptor antagonist antibody), recombinant hirudin, andthrombin inhibitors such as Angiomax™, from Biogen, Inc., Cambridge,Mass.; and thrombolytic agents, such as urokinase, e.g., Abbokinase™from Abbott Laboratories Inc., North Chicago, Ill., recombinanturokinase and pro-urokinase from Abbott Laboratories Inc., tissueplasminogen activator (Alteplase™ from Genentech, South San Francisco,Calif. and tenecteplase (TNK-tPA).

Examples of such cytostatic or antiproliferative agents includerapamycin and its analogs including everolimus, zotarolimus, i.e.,3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)-9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-Hexadecahydro-9,27-dihydroxy-3-[(1R)-2-[(1S,3R,4R)-3-methoxy-4-tetrazol-1-yl)cyclohexyl]-1-methylethyl]-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-23,27-epoxy-3H-pyrido[2,1-c][1,4]oxaazacyclohentriacontine-1,5,11,28,29(4H,6H,31H)-pentone;23,27-Epoxy-3Hpyrido[2,1-c][1,4]oxaazacyclohentriacontine-1,5,11,28,29(4H,6H,31H)-pentone,tacrolimus and pimecrolimus, angiopeptin, angiotensin converting enzymeinhibitors such as captopril, e.g, Capoten® and Capozide® fromBristol-Myers Squibb Co., Stamford, Conn., cilazapril or lisinopril,e.g., Prinivil® and Prinzide® from Merck & Co., Inc., WhitehouseStation, N.J.; calcium channel blockers such as nifedipine, amlodipine,cilnidipine, lercanidipine, benidipine, trifluperazine, diltiazem andverapamil, fibroblast growth factor antagonists, fish oil (omega 3-fattyacid), histamine antagonists, lovastatin, e.g. Mevacor® from Merck &Co., Inc., Whitehouse Station, N.J. In addition, topoisomeraseinhibitors such as etoposide and topotecan, as well as antiestrogenssuch as tamoxifen may be used.

Examples of such anti-inflammatories include colchicine andglucocorticoids such as betamethasone, cortisone, dexamethasone,budesonide, prednisolone, methylprednisolone and hydrocortisone.Non-steroidal anti-inflammatory agents include flurbiprofen, ibuprofen,ketoprofen, fenoprofen, naproxen, diclofenac, diflunisal, acetominophen,indomethacin, sulindac, etodolac, diclofenac, ketorolac, meclofenamicacid, piroxicam and phenylbutazone.

Examples of such antineoplastics include alkylating agents includingaltretamine, bendamucine, carboplatin, carmustine, cisplatin,cyclophosphamide, fotemustine, ifosfamide, lomustine, nimustine,prednimustine, and treosulfin, antimitotics including vincristine,vinblastine, paclitaxel, e.g., TAXOL™ by Bristol-Myers Squibb Co.,Stamford, Conn., docetaxel, e.g., Taxotere® from Aventis S.A.,Frankfort, Germany, antimetabolites including methotrexate,mercaptopurine, pentostatin, trimetrexate, gemcitabine, azathioprine,and fluorouracil, and antibiotics such as doxorubicin hydrochloride,e.g., Adriamycin® from Pharmacia & Upjohn, Peapack, N.J., and mitomycin,e.g., Mutamycin® from Bristol-Myers Squibb Co., Stamford, Conn., agentsthat promote endothelial cell recovery including Estradiol.

Additional drugs which may be utilized in this application includeinhibitors of tyrosine kinase such as RPR-101511A, PPAR-alpha agonistssuch as Tricor™ (fenofibrate) from Abbott Laboratories Inc., NorthChicago, Ill., endothelin receptor antagonists including astrasentan(ABT-627) having general formula C₂₉H₃₈N₂O₆.ClH, and the followingstructural formula

from Abbott Laboratories Inc., North Chicago, Ill.; matrixmetalloproteinase inhibitors such as ABT-518 having general formulaC₂₁H₂₂F₃NO₈S and having the following structural formula

from Abbott Laboratories Inc., North Chicago, Ill., antiallergic agentssuch as permirolast potassium nitroprusside, phosphodiesteraseinhibitors, prostaglandin inhibitors, suramin, serotonin blockers,steroids, thioprotease inhibitors, triazolopyrimidine, and nitric oxide.

When at least one beneficial agent is utilized in the invention, thebeneficial agent includes, but is not limited to, at least one ofantiulcer/antireflux agents, and antinauseants/antiemetics, and anycombinations thereof. When at least one beneficial agent is utilized inthe invention, the beneficial agent includes, but is not limited to, atleast one of phenyl salicylate, β-estradiol, testosterone, progesterone,cyclosporin A, carvediol, vindesine, folic acid, thrombospondinmimetics, estradiol, metrizamide, iopamidol, iohexol, iopromide,iobitridol, iomeprol, iopentol, ioversol, ioxilan, iodixanol, iotrolanand pro-drugs, analogs, derivatives, and any combinations thereof.

While the above beneficial agents are known for their preventive andtreatment properties, the substances or agents are provided by way ofexample and are not meant to be limiting. Further, other beneficialagents that are currently available or may be developed are equallyapplicable for use with embodiments of the invention.

The terms “biocompatible” and “biocompatibility” when used herein areart-recognized and mean that the referent is neither itself toxic to ahost (e.g., an animal or human), nor degrades (if it degrades) at a ratethat produces byproducts (e.g., monomeric or oligomeric subunits orother byproducts) at toxic concentrations, causes inflammation orirritation, or induces an immune reaction, in the host. It is notnecessary that any subject composition have a purity of 100% to bedeemed biocompatible. Hence, a subject composition may comprise 99%,98%, 97%, 96%, 95%, 90% 85%, 80%, 75% or even less of biocompatibleagents, e.g., including polymers and other materials and excipientsdescribed herein, and still be biocompatible.

The term “preventing” is art-recognized, and when used in relation to acondition, including a local recurrence (e.g., pain), a diseaseincluding cancer, a syndrome complex including heart failure or anyother medical condition, is well understood in the art, and includesadministration of a composition which reduces the frequency of, ordelays the onset of, symptoms of a medical condition in a subjectrelative to a subject which does not receive the composition. Thus,prevention of cancer includes, for example, reducing the number ofdetectable cancerous growths in a population of patients receiving aprophylactic treatment relative to an untreated control population,and/or delaying the appearance of detectable cancerous growths in atreated population versus an untreated control population, e.g., by astatistically and/or clinically significant amount. Prevention of aninfection includes, for example, reducing the number of diagnoses of theinfection in a treated population versus an untreated controlpopulation, and/or delaying the onset of symptoms of the infection in atreated population versus an untreated control population. Prevention ofpain includes, for example, reducing the magnitude of, or alternativelydelaying, pain sensations experienced by subjects in a treatedpopulation versus an untreated control population.

The term “polymer” is intended to include a product of a polymerizationreaction inclusive of homopolymers, copolymers, terpolymers, etc.,whether natural or synthetic, including random, alternating, block,graft, branched, cross-linked, blends, compositions of blends andvariations thereof. The polymer may be in true solution, saturated, orsuspended as particles or supersaturated in the beneficial agent. Thepolymer can be biocompatible, or biodegradable. For purpose ofillustration and not limitation, the polymeric material includephosphorylcholine linked macromolecules, including a macromoleculecontaining pendant phosphorylcholine groups such aspoly(MPC.sub.w:LMA.sub.x:HPMA.sub.y:TSMA.sub.z), where MPC is2-methacryoyloxyethylphosphorylcholine, LMA is lauryl methacrylate, HPMAis hydroxypropyl methacrylate and TSMA is trimethoxysilylpropylmethacrylate, polycaprolactone, poly-D,L-lactic acid, poly-L-lacticacid, poly(lactide-co-glycolide), poly(hydroxybutyrate),poly(hydroxybutyrate-co-valerate), polydioxanone, polyorthoester,polyanhydride, poly(glycolic acid), poly(glycolic acid-co-trimethylenecarbonate), polyphosphoester, polyphosphoester urethane, poly(aminoacids), cyanoacrylates, poly(trimethylene carbonate),poly(iminocarbonate), polyalkylene oxalates, polyphosphazenes,polyiminocarbonates, and aliphatic polycarbonates, fibrin, fibrinogen,cellulose, starch, collagen, Parylene.RTM., Parylast.RTM., polyurethaneincluding polycarbonate urethanes, polyethylene, polyethyleneterapthalate, ethylene vinyl acetate, ethylene vinyl alcohol, siliconeincluding polysiloxanes and substituted polysiloxanes, polyethyleneoxide, polybutylene terepthalate-co-PEG, PCL-co-PEG, PLA-co-PEG,polyacrylates, polyvinyl pyrrolidone, polyacrylamide, and combinationsthereof. Non-limiting examples of other suitable polymers includethermoplastic elastomers in general, polyolefin elastomers, EPDM rubbersand polyamide elastomers, and biostable plastic material includingacrylic polymers, and its derivatives, nylon, polyesters and expoxies.Other polymers include pendant phosphoryl groups as disclosed in U.S.Pat. Nos. 5,705,583 and 6,090,901 to Bowers et al. and U.S. Pat. No.6,083,257 to Taylor et al., and U.S. Pat. Nos. 5,705,583 and 6,090,901teach phosphorylcholine polymers (including PC-1036 and PC-2126), whichare all incorporated herein by reference.

The term “pro-drug,” as used herein, refers to compounds, which aretransformed in vivo to the parent compound of the formula above, forexample, by hydrolysis in blood. A thorough discussion is provided by T.Higuchi and V. Stella, “Pro-drugs as Novel Delivery systems,” Vol. 14 ofthe A.C.S. symposium Series, and in Edward B. Roche, ed., “BioreversibleCarriers in Drug Design.” American Pharmaceutical Association andPergamon Press, 1987, both of which are incorporated herein byreference.

The term “subject” as used herein, refers to any warm-blooded animal andmammals including, but not limited to, humans, pigs, dogs, monkeys,cows, goats, sheep, horses, rats, mice, and guinea pigs.

The term “treating” is art-recognized and includes preventing a disease,disorder or condition from occurring in an animal which may bepredisposed to the disease, disorder and/or condition but has not yetbeen diagnosed as having it; inhibiting the disease, disorder orcondition, e.g., impeding its progress; and relieving the disease,disorder, or condition, e.g., causing regression of the disease,disorder and/or condition. Treating the disease or condition includesameliorating at least one symptom of the particular disease orcondition, even if the underlying pathophysiology is not affected, suchas treating the pain of a subject by administration of an analgesicagent even though such agent does not treat the cause of the pain.

The following are working and prophetic examples of embodiments of theabove aspects and are by no means limiting. Zotarolimus (ABT-578),rapamycin, siroilums (rapamycin), biolimus A-9, everolimus, paclitaxel,dexamethasone, and estradiol are all being proposed for use indrug-eluting stents to reduce restenosis in percutaneous intervention ofcoronary arteries. Since local drug delivery and tissue uptake are afunction of drug solubility and lipophilicity, a study was conducted todetermine the precise physicochemical profile for these compounds.Solubilities of the drug molecules (both crystalline and amorphousforms) and lipophilicity (LogP), were determined. The results of thesestudies provide a better understanding of the in vivo pharmacokineticsof drug-eluting stents.

Methods of Determining Solubility and Partition Coefficients of VariousDrugs

“Solubility” is based on a standard measure used in medicinal chemistry.The octanol-water partition coefficient (P) is the ratio of distributionof a compound in a mixture of 1-octanol and H₂O. LogP is the base 10logarithm of the partition coefficient.

$P = \frac{C\left( {n - {octanol}} \right)}{C({water})}$

Compounds with LogP values greater than about 1 are consideredlipophilic (greater solubility in 1-octanol versus H₂O). One can use avariety of computerized protocols to perform calculated estimates of theLogP value. One such computer program is ChemDraw Pro Version 5.0 fromCambridgeSoftCorporation. To calculate the LogP coefficient one can usethe Crippen's fragmentation method (Crippen et. al., J. Chem. Inf.Comput. Sci. 1987, 27, 21).

The shake-flask method was used in both the solubility and partitioncoefficient studies. Preliminary analyses were conducted to evaluate theoptimum conditions for both methods. For the partition coefficientmethodology, drug was dissolved in an organic phase (n-octanol),followed by the addition of buffered water to extract the drug from theorganic phase. Ultimately, the drug concentrations in both phases reachan equilibrium determined by the partition coefficient of the drugcompound. For solubility testing, an initial evaluation was conducted toensure full separation of drug particles from the saturated solution,and to avoid adsorption of drug by the experimental apparatus. Themeasurements were performed at multiple equilibration times (from 2hours up to 5 days). Concentrations of all drug compounds were assayedby validated HPLC methods.

In the measurement of the partition coefficient (octanol/water),preliminary studies were conducted to determine the optimum drugconcentration for each test, and the appropriate time for establishingthe partition equilibrium. All experiments were carried out by twodifferent analysts and on multiple drug lots.

Results are shown in the FIG. 20 (DES=drug-eluting stents). Partitioncoefficients vary by over a factor of 400 between drugs. The resultsindicated that the “limus” drugs zotarolimus and rapamycin are the mostlipophilic compounds in the group tested. Of these, zotarolimus is morethan two times as lipophilic as rapamycin. The results of theseexperiments indicate that zotarolimus, a rapamycin analog in currentclinical trials for delivery from the ZoMaxx™ coronary drug-elutingstent (Abbott Vascular Inc.) is much less soluble in water thanamorphous rapamycin, and is the most lipophilic of all DES drugs tested.This characteristic suggests preferential uptake of zotarolimus into thevessel wall, with minimal loss of the drug to the more hydrophilicsystemic circulation. Lipophilicity improves drug transport into tissuecells of the arterial wall and improves tissue retention of the drug.

Drug delivery in DES ideally occurs with predominate tissue uptake,however, drug also partitions into the blood. Consequently, high aqueoussolubility may have a negative impact on local drug bioavailability. Ithas been determined by the above tests that lipophilicity and solubilityare controlling factors in DES drug delivery.

While most drug-eluting stents have amorphous drugs mixed in a polymermatrix, the bulk DES drug exists in either amorphous or crystallineforms. Therefore, solubility data on DES drugs was investigated for boththe amorphous and crystalline forms. It was found that rapamycin can beeither amorphous or crystalline, zotarolimus is amorphous, andpaclitaxel has two crystal forms. Aqueous solubility of amorphous DESdrugs follow the increasing order: paclitaxel, zotarolimus, rapamycin,and dexamethasone (crystalline).

A transfer coefficient, T, can be defined as P divided by S, where Pequals the partition coefficient and S equals the equilibrium aqueoussolubility, (μg/ml) as shown in FIG. 21. These studies demonstrationthat the transfer coefficient for the DES drug studied are in the orderzotarolimus>>paclitaxel>>rapamycin>dexamethasone. Where S equals theequilibrium aqueous solubility of the amorphous form of the drug werepossible.

The aspects of the invention further include at least onepharmaceutically acceptable carrier or excipient, wherein the medicaldevice is associated with the pharmaceutically acceptable carrier orexcipient. In embodiments, the pharmaceutically acceptable carrier orexcipient is a polymer. In other embodiments, the pharmaceuticallyacceptable carrier or excipient is an agent. When a polymer is utilizedas the pharmaceutically acceptable carrier or excipient, the deliverymechanism of the first lipophilic agent includes polymer hydrationfollowed by dissolution of the first lipophilic agent, and wherein thefirst lipophilic agent is thereafter delivered into the body lumen.Another delivery mechanism includes the first lipophilic agent/polymermatrix controlling the elution rate of the first lipophilic agent to thebody lumen.

Embodiments of the invention further include at least one of thefollowing: at least one second lipophilic agent, at least one lipophilicprodrug, at least one beneficial agent, at least one lipophilicpenetration enhancer, and any combination thereof. In embodiments when alipophilic penetration enhancer is utilized, the enhancer is apharmaceutical agent.

A further embodiment of the invention is to provide drug delivery to themyocardial wall to reduce the area or extent of ischemic or infarctedcardiac tissue. Examples of agents to be used for this purpose include,but are not limited to, calcium channel blockers (nifedipine, diltiazem,nicardipine and verapamil), beta-adrenergic blocking agents (nadolol,metoprolol, propranolol, atenolol and esmolol) and nitrates(nitroglycerin and isosorbide dinitrate). Yet another embodiment of theinvention is to deliver drug to hypokinetic or akinetic regions of themyocardial wall to improve contractility of the cardiac muscle in thetreatment of heart failure. Drug examples include, but are not limitedto carvedilol, an adrenergic antagonist with nonselective beta- anda1-receptor blocking properties, cardiac glycosides such as digitalis,and calcium sensitizers such as levosimendan. Delivery of agents tostabilize vulnerable plaque, such as inhibitors of matrixmetalloproteinases (batimistat, prinomastat, marimistat and ABT-518) orthe macrolide antibiotic azithromycin, may also be delivered. Tomaintain patency of body lumens including, but not limited to, theurethra, the delivery of chemotherapeutic agents such as alkylatingagents and antimetabolites may be utilized.

The concentration of the first lipophilic agent delivered into the bodylumen or desired targeted area is a therapeutically effective amount.When a second lipophilic agent is utilized, the concentration of thesecond lipophilic agent in combination with the first lipophilic agentis delivered into the body lumen or desired targeted area in atherapeutically effective amount.

When utilized in the invention, the first lipophilic agent and/or secondlipophilic agent zotarolimus having the structures as follows.

The body lumen in the application includes, but is not limited to, avessel wall, either arterial or venous. In other embodiments, the bodylumen includes, but is not limited to, at least one of a vessel wall, acoronary artery, esophageal lumen, or a urethra. For example, such as,the first lipophilic agent/medical device is placed adjacent to a bodylumen (coronary arteries) and a therapeutically effective amount of thefirst lipophilic agent is delivered into said coronary arteries and isdiffused into the pericardial sac in a drug delivery system. Inembodiments, the invention provides for substantially uniform dugdelivery of the lipophilic agent to the myocardium and/or is useful forthe treatment and/or prevention of vascular diseases in a subject. Inembodiments, the lipophilic agent is continuously delivered to theepicardium and/or pericardial sac.

Embodiments of the first lipophilic agent includes agents with partitioncoefficients greater than 20,000. In embodiments of the invention, thefirst lipophilic agent includes transfer coefficients of at leastapproximately 10,000 (μg/mL)⁻¹. In other embodiments, the firstlipophilic agent includes transfer coefficient of at least approximately15,000 (μg/mL)⁻¹. Embodiments of the first lipophilic agent includecompounds having LogP of at least approximately 4.3, as shown in FIG.24. The first lipophilic agent includes partition coefficient greaterthan 20,000 P and the lipophilic agent includes a solubility of lessthan about 30 ug/ml. In embodiments, the first lipophilic agent isamorphous.

FIG. 22 is a rabbit study comparing the drug concentration in rabbittissue by drug elution from the ZoMaxx™ stent vs. the Cypher® stent. Thedosage delivery of the first lipophilic agent into the vascular tissueranges from about 15 μg/g to about 150 μg/g over a period of up to about5 days. In other embodiments, the dosage delivery of the firstlipophilic agent into the vascular tissue ranges from about 15 μg/g toabout 80 μg/g over a period from about 5 to up to about 15 days. At notime points between 0 and 15 days, the comparator Cypher® stent reachesconcentrations of rapamycin higher than 10 μg/g. Still in otherembodiments, the dosage delivery of the first lipophilic agent into thevascular tissue ranges from about 5 μg/g to about 60 μg/g over from 15to up to about 28 days. Still in other embodiments, the dosage deliveryof the first lipophilic agent is always greater than 5 times the dosedelivery of the comparative Cypher® stent at the 28 day point.

FIG. 23 is a from the same rabbit study comparing the drug levels inrabbit blood for ZoMaxx™ stent vs. Cypher® stent. The blood levels ofrapamycin eluted from the Cypher® stents are consistently significantlyhigher than the blood levels of zotarolimus eluted from the ZoMaxx™stents.

FIG. 25 is a graph demonstrating blood, liver, kidney, artery andmyocardial concentrations of zotarolimus eluted from ZoMaxx™ tents in apig model Zotarolimus is delivered in substantial concentrations to thearterial tissue adjacent to the stent placement at all periods out to 28days. Unexpectedly, zotarolimus also reaches therapeutically significantconcentrations in the distal myocardium, the unstent myocardium, and inthe subjacent myocardium and in unstented and distal coronary arteriesand maintains those concentrations throughout the 28 day course of theexperiment.

In embodiments of the invention, the medical device includes, but is notlimited to, an endovascular medical device. In embodiments, the medicaldevice includes intracoronary medical devices including at least one ofstents, drug delivery catheters, grafts, and drug delivery balloonsutilized in a subjects' vasculature. When the medical device is a stent,the stent includes peripheral stents, peripheral coronary stents,degradable coronary stents, non-degradable coronary stents,self-expanding stents, balloon-expanded stents, and esophageal stents.In other embodiments, the medical device includes at least one of, butis not limited to, arterio-venous grafts, by-pass grafts, penileimplants, vascular implants and grafts, intravenous catheters, smalldiameter grafts, artificial lung catheters, electrophysiology catheters,bone pins, suture anchors, blood pressure and stent graft catheters,breast implants, benign prostatic hyperplasia and prostate cancerimplants, bone repair/augmentation devices, breast implants, orthopedicjoint implants, dental implants, implanted drug infusion tubes,oncological implants, pain management implants, neurological catheters,central venous access catheters, catheter cuff, vascular accesscatheters, urological catheters/implants, atherectomy catheters, clotextraction catheters, PTA catheters, PTCA catheters, stylets (vascularand non-vascular), drug infusion catheters, angiographic catheters,hemodialysis catheters, neurovascular balloon catheters, thoracic cavitysuction drainage catheters, electrophysiology catheters, stroke therapycatheters, abscess drainage catheters, biliary drainage products,dialysis catheters, central venous access catheters, and parentalfeeding catheters.

Yet in other embodiments, the medical device includes at least one of,but is not limited to, either arterial or venous, pacemakers, vasculargrafts, sphincter devices, urethral devices, bladder devices, renaldevices, gastroenteral and anastomotic devices, vertebral disks,hemostatic barriers, clamps, surgicalstaples/sutures/screws/plates/wires/clips, glucose sensors, bloodoxygenator tubing, blood oxygenator membranes, blood bags, birthcontrol/IUDs and associated pregnancy control devices, cartilage repairdevices, orthopedic fracture repairs, tissue adhesives, tissue sealants,tissue scaffolds, CSF shunts, dental fracture repair devices,intravitreal drug delivery devices, nerve regeneration conduits,electrostimulation leads, spinal/orthopedic repair devices, wounddressings, embolic protection filters, abdominal aortic aneurysm graftsand devices, neuro aneurysm treatment coils, hemodialysis devices,uterine bleeding patches, anastomotic closures, in vitro diagnostics,aneurysm exclusion devices, neuropatches, vena cava filters, urinarydilators, endoscopic surgical and wound drainings, surgical tissueextractors, transition sheaths and dialators, coronary and peripheralguidewires, circulatory support systems, tympanostomy vent tubes,cerebro-spinal fluid shunts, defibrillator leads, percutaneous closuredevices, drainage tubes, bronchial tubes, vascular coils, vascularprotection devices, vascular intervention devices including vascularfilters and distal support devices and emboli filter/entrapment aids, AVaccess grafts, surgical tampons, drug delivery capsule and cardiacvalves. For example, such as, the first lipophilic agent/medical deviceis placed adjacent to a body lumen (arteries, veins or grafts) and atherapeutically effective amount of the first lipophilic agent isdelivered into said arteries, veins or grafts and is diffused into thepericardial sac in a drug delivery system. In embodiments, the inventionprovides for substantially uniform dug delivery of the lipophilic agentto the myocardium and/or is useful for the treatment and/or preventionof vascular diseases in a subject. The medical device is permanently ortemporarily implanted into a subject.

In accordance with the invention, a medical device is provided having aninterventional component that is loaded with a beneficial agent that isassociated with a hydration inhibitor to control the delivery of thebeneficial agent in a patient. As used herein “medical device” refersbroadly to any device that is deployed in a patient. In an embodiment,the invention is directed to a medical device having controlled deliveryof a beneficial agent for the treatment and prevention of cardio,vascular or other intraluminal diseases. The medical device is suitablefor intraluminal delivery or implantation.

As is known in the art, such devices can comprise one or moreinterventional components. For purposes of illustration and notlimitation, examples of such medical devices include stents, grafts,stent-grafts, valves, filters, coils, staples, sutures, guidewires,catheters, catheter balloons, and the like. In an embodiment, theinterventional component is an interventional component having a firstcross-sectional dimension for the purpose of delivery and a secondcross-sectional dimension after deployment and can be deployed by knownmechanical techniques including balloon expansion deployment techniques,or by electrical or thermal actuation, or self-expansion deploymenttechniques, as well known in the art. For example, and as embodiedherein, representative embodiments of a stent, stent-graft or similarinterventional component are disclosed in U.S. Pat. No. 4,733,665 toPalmaz; U.S. Pat. No. 6,106,548 to Roubin et al.; U.S. Pat. No.4,580,568 to Gianturco; U.S. Pat. No. 5,755,771 to Penn et al.; and U.S.Pat. No. 6,033,434 to Borghi, are all incorporated herein by reference.It is recognized, however, that the interventional component can be anytype of implantable or deployable interventional component capable ofbeing loaded with beneficial agent.

The interventional component can be in an expanded or unexpanded stateduring the loading of beneficial agent. The underlying structure of theinterventional component can be virtually any construction and theinterventional component can be composed any suitable materialincluding, but not limited to, stainless steel, “MP35N,” “MP20N,”elastinite (Nitinol), tantalum, nickel-titanium alloy, platinum-iridiumalloy, chromium-cobalt alloy, gold, magnesium, polymer, ceramic, tissue,or combinations thereof. “MP35N” and “MP20N” are understood to be tradenames for alloys of cobalt, nickel, chromium and molybdenum availablefrom Standard Press Steel Co., Jenkintown, Pa. “MP35N” consists of 35%cobalt, 35% nickel, 20% chromium, and 10% molybdenum. “MP20N” consistsof 50% cobalt, 20% nickel, 20% chromium and 10% molybdenum. Similarly,the interventional component can be made from bioabsorbable or biostablepolymers. In some embodiments, the surface of the interventionalcomponent is porous or impervious, or include one or more reservoirs orcavities formed therein for purpose of retaining beneficial agenttherein as is known in the art.

The interventional component can be fabricated utilizing any number ofmethods known in the art. For example, the interventional component canbe fabricated from a hollow or formed tube that is machined usinglasers, electric discharge milling, chemical etching or other knowntechniques. Alternatively, the interventional component can befabricated from a sheet or formed of a wire or filament construction asknown in the art.

In accordance with the present invention, the interventional componentis loaded with beneficial agent to be delivered therefrom when deployedwithin the patient. “Beneficial agent” as used herein, generally refersto any compound, mixture of compounds, or composition of matterconsisting of a compound, which produces a beneficial or useful resultin a patient. The beneficial agent has a first LogP value.

The symbol “P” of “LogP” is the calculated partition coefficient of achemical substance, which is a measure of the way in which a compoundwill partition itself between the octanol and water phases in thetwo-phase octanol-water system, and thus an indicator of certain typesof biological activity. Specifically, P is the ratio of theconcentration (in moles per liter) of the compound in the octanol phaseto that in the water phase at infinite dilution. The solubility isusually expressed as base 10 logarithm of the partition coefficient,LogP. LogP and methods for calculating it are well known to thoseskilled in the art. The LogP value can be calculated by the methoddescribed in (Hansch C. and Leo A. “Substituent Constants forCorrelation Analysis in Chemistry and Biology” Wiley, N.Y., 1979). Thecharacteristic of being “relatively less hydrophilic” or “relativelymore hydrophilic” as disclosed herein is determined according to theLogP value calculations. A discussion of methods of measurement andaccuracy considerations for LogP is found in Sangster, J., J. Phys.Chem. Ref. Data, 18, 1111, 1989, incorporated herein by reference. LogPvalues can also be calculated by the method described in Hansch C. andLeo A. “Substituent Constants for Correlation Analysis in Chemistry andBiology” Wiley, N.Y., 1979. Other discussions of LogP may be found inthe following documents, incorporated herein by reference: Mackay, D.,Shiu, W. Y., and Ma, K. C., Illustrated Handbook of Physical-ChemicalProperties and Environmental Fate for Organic Chemicals, LewisPublishers/CRC Press, Boca Raton, Fla., 1992; Shiu, W. Y., and Mackay,D., J. Phys. Chem. Ref. Data, 15, 911, 1986; Pinsuwan, S., Li, L., andYalkowsky, S. H., J. Chem. Eng. Data, 40, 623, 1995; Solubility DataSeries, International Union of Pure and Applied Chemistry, Vol. 20,Pergamon Press, Oxford, 1985; Solubility Data Series, InternationalUnion of Pure and Applied Chemistry, Vol. 38, Pergamon Press, Oxford,1985; Miller, M. M., Ghodbane, S., Wasik, S. P., Tewari, Y. B., andMartire, D. E., J. Chem. Eng. Data, 29, 184, 1984.

LogP is a widely used parameter for correlating biological effects oforganic substances. It is a property of the two-phase system in whichwater and 1-octanol are in equilibrium at a fixed temperature and thesubstance is distributed between the water-rich and octanol-rich phases.

Generally, the greater the LogP value of a compound or agent, the lesshydrophilic the compound or agent. It also has been determined that acompound or agent having a greater LogP value (i.e., a “relatively lesshydrophilic agent”) will inhibit hydration of the second compound oragent having a lower LogP value (i.e., a “relatively more hydrophilicagent”). Thus, and in accordance with embodiments of the invention, arelatively less hydrophilic agent can be used as a hydration inhibitorfor a relatively more hydrophilic beneficial agent, which is to bedelivered from an interventional component as a beneficial agent,wherein the hydration inhibitor has a LogP value that is greater thanthe LogP value of the beneficial agent. In embodiments, the LogP valueof the hydration inhibitor is at least 0.1 units greater than thebeneficial agent and at least 0.5 units greater than the beneficialagent. Particularly, and in an embodiment of the invention, the LogPvalue of the beneficial agent is less than 4.5 units, and morepreferably it is less than 3.0 units. See “CRC Handbook of Chemistry andPhysics,” 3rd Electronic Edition, 2000. However, it is possible for acompound to serve as a hydration inhibitor of the elution of a givenbeneficial agent according to embodiments of the invention when thebeneficial agent's LogP value is less than that of the given hydrationinhibitor. Although those skilled in the art are familiar with LogPvalues and the well-known methods for calculation thereof, for purposeof illustration, and not limitation, Table 1 provides a representativesummary of LogP values for several suitable beneficial agents for usewith embodiments of the invention.

TABLE 1 Beneficial Agent LogP Values Probucol >8 Linolenic acid >6Linoleic acid >6 Stearic acid >6 Oleic acid >6 Paclitaxel >5 Danazol 4.5Rapamycin >4.5 Zotarolimus >4.5 Tacrolimus >4.5 Fenofibrate >4.5Indomethacin 4.3 Phenyl salicylate 4.1 B-estradiol 4 Vinblastine 3.6ABT-627 3.4 Testosterone 3.3 Progesterone 3.2 Paclitaxel >3 CyclosporinA 2.9 Vincristine 2.6 Carvedilol 1.97 Dexamethasone ~1.9-2.2 Vindesine1.3 Dipyridamole 1-2 Methotrexate −1.85

A variety of suitable beneficial agents for delivery of aninterventional component are well known. For example, and notlimitation, various suitable beneficial agents having a LogP valueinclude markers, such as, for example, a radiopaque dyes or particles,drugs, such as, for example, pharmaceutical and therapeutic agents, andinorganic or organic drugs without limitation. The agent or drug can bein various forms, components of molecular complexes,pharmacologically-acceptable salts such as hydrochloride, hydrobromide,sulfate, phosphate, nitrate, borate, acetate, maleate, tartrate andsalicylate.

For purposes of illustration and not limitation, the drug or agentincludes antithrombotics, anticoagulants, antiplatelet agents,anti-lipid agents, thrombolytics, antiproliferatives,anti-inflammatories, agents that inhibit hyperplasia, smooth muscle cellinhibitors, antibiotics, growth factor inhibitors, cell adhesioninhibitors, cell adhesion promoters, antimitotics, antifibrins,antioxidants, antineoplastics, agents that promote endothelial cellrecovery, antiallergic substances, viral vectors, nucleic acids,monoclonal antibodies, antisense compounds, oligionucleotides, cellpermeation enhancers, pro-drugs and combinations thereof. Otherbeneficial agents include but are not limited to nucleic acids thatencode a pharmaceutically useful peptide or an anti-senseoligo-nucleotide used to control a gene of interest in a cell.

Examples of specific beneficial agents of interest include indomethacin,phenyl salicylate, β-estradiol, vinblastine, ABT-627 (atrasentan),testosterone, progesterone, paclitaxel, cyclosporin A, vincristine,carvedilol, vindesine, dipyridamole, methotrexate, folic acid,thrombospondin mimetics, estradiol, dexamethasone, metrizamide,iopamidol, iohexol, iopromide, iobitridol, iomeprol, iopentol, ioversol,ioxilan, iodixanol, iotrolan and pro-drugs, analogs, derivatives, orcombinations thereof. Beneficial agents can have various art known formsincluding solutions, dispersions, pastes, particles, granules,emulsions, suspensions and powders. The beneficial agent typically isassociated with the hydration inhibitor as a mixture, although can beassociated as a separate application, including an overcoat or layerwhen a beneficial agent is used as the hydration inhibitor as disclosedfurther below.

While the foregoing beneficial agents are well known for theirpreventive and treatment properties, the substances or agents areprovided by way of example and not limitation. Further, other beneficialagents with suitable LogP values that are currently available or can bedeveloped are equally applicable for use with the invention.

Further in accordance with embodiments of the invention, an effectiveamount of hydration inhibitor is associated with the beneficial agent tobe delivered from the interventional component so as to control deliverytherefrom. The term “hydration inhibitor” as used herein refers to asuitable compound or agent or the like having a LogP value greater thanthat of the beneficial agent. The hydration inhibitor is thus relativelyless hydrophilic than the beneficial agent, and controls delivery of thebeneficial agent by retarding, inhibiting or otherwise sustaining therate in which the beneficial agent would be delivered from theinterventional component without the hydration inhibitor associatedtherewith. Delivery of the beneficial agent from the interventionalcomponent occurs by any of a variety of know mechanisms, includingelution, diffusion, dissolution, permeation or other transportmechanisms in vivo.

Generally, “effective amount” of hydration inhibitor refers to an amountsufficient to inhibit hydration of the beneficial agent to be deliveredfrom the interventional component. For example, it is well known todetermine hydration as a measure of optical contact angle, wherein acontact angle of about 30° is indicative of a hydrophilic compound and acontact angle of greater than about 50° is indicative of a hydrophobiccompound. Optical contact angle and methods for calculating it are wellknown to those skilled in the art using standard evaluation methods andis disclosed in “McGraw-Hill Encyclopedia of Chemistry,” 538 (Sybil P.Parker, 2nd ed. 1993) and “Remington's Pharmaceutical Sciences,” 256-7and 294-5 (Arthur Osol et al. eds., 16th ed. 1980), herein incorporatedby reference. As such, an effective amount of hydration inhibitor isrecognized to be a sufficient amount to shift the optical contact angleof the beneficial agent in association with the hydration inhibitor toat least about 50° and to at least about 70°.

For purposes of illustration and not limitation, the hydration inhibitorincludes beneficial agents (including markers), polymeric materials,additives and combinations thereof. When a second “beneficial agent” isused as the hydration inhibitor, the LogP value of the second beneficialagent must be greater than the LogP value of the first beneficial agent.Examples of such beneficial agent hydration inhibitors includeantioxidants, antithrombotics, anticoagulants, antiplatelet agents,anti-lipid agents, thrombolytics, antiproliferatives,anti-inflammatories, agents that inhibit hyperplasia, smooth muscle cellinhibitors, antibiotics, growth factor inhibitors, cell adhesioninhibitors, cell adhesion promoters, antimitotics, antifibrins,antioxidants, antineoplastics, agents that promote endothelial cellrecovery, antiallergic substances, viral vectors, nucleic acids,monoclonal antibodies, antisense compounds, oligionucleotides, cellpermeation enhancers, radiopaque agents markers and combinationsthereof.

Non-limiting examples of specific beneficial agent useful as hydrationinhibitors include paclitaxel, rapamycin, rapamycin derivatives,pimecrolimus, everolimus, fenofibrate, carvedilol, taxoteres,tacrolimus, butylated hydroxytoluene, butylated hydroxyanisole, vitaminE, danazol, probucol, tocopherols, tocotrienols, zotarolimus, ABT-627and analogs, derivatives, or combinations thereof. The following is thechemical structure of ABT-627

and the chemical structure of zotarolimus is

A detailed discussion of ABT-627 (atrasentan) is available inPCT/US02/28776, filed Sep. 10, 2002, and zotarolimus in U.S. Pat. Nos.6,015,815 and 6,329,386, the disclosure of each is incorporated byreference herein.

Although the hydration inhibitor is associated with the beneficial agentas a mixture, in an alternative embodiment, wherein the hydrationinhibitor is a second beneficial agent, the hydration inhibitor can beassociated as an overcoat or encapsulating layer covering at least aportion of the first beneficial agent.

Polymeric materials suitable as hydration inhibitors are typically aproduct of a polymerization reaction inclusive of homopolymers,copolymers, terpolymers, etc., whether natural or synthetic, includingrandom, alternating, block, graft, branched, cross-linked, blends,compositions of blends and variations thereof. The polymer can be intrue solution, saturated, or suspended as particles or supersaturated inthe beneficial agent. The polymer is biocompatible, and can bebiodegradable.

Examples of such polymeric materials include phosphorylcholine,polycaprolactone, poly-D,L-lactic acid, poly-L-lactic acid,poly(lactide-co-glycolide), poly(hydroxybutyrate),poly(hydroxybutyrate-co-valerate), polydioxanone, polyorthoester,polyanhydride, poly(glycolic acid), poly(glycolic acid-co-trimethylenecarbonate), polyphosphoester, polyphosphoester urethane, poly(aminoacids), cyanoacrylates, poly(trimethylene carbonate),poly(iminocarbonate), polyalkylene oxalates, polyphosphazenes,polyiminocarbonates, and aliphatic polycarbonates, fibrin, fibrinogen,cellulose, starch, collagen, Parylene®, Parylast®, polyurethane,polycarbonate urethanes, polyethylene, polyethylene terapthalate,ethylene vinyl acetate, ethylene vinyl alcohol, silicone polysiloxanes,substituted polysiloxanes, polyethylene oxide, polybutyleneterepthalate-co-PEG, PCL-co-PEG, PLA-co-PEG, polyacrylates, polyvinylpyrrolidone, polyacrylamide, thermoplastic elastomers, polyolefinelastomers, EPDM rubbers, polyamide elastomers, biostable plastic,acrylic polymers, nylon, polyesters, epoxies and derivatives orcombination thereof.

In an embodiment, the polymeric material has a zwitterionic pendantgroup. In some of the embodiments, the polymer is phosphorylcholinedisclosed in U.S. Pat. Nos. 5,705,583 and 6,090,901 to Bowers et al. andU.S. Pat. No. 6,083,257 to Taylor et al, the disclosure of each isincorporated in entirety by reference herewith.

As noted above, the beneficial agent can include a beneficial agent andpolymer mixture. In accordance with the method of the invention, thefirst beneficial agent can correspond to a beneficial agent-polymermixture having a concentration of polymer to effect the delivery rate ofthe particular beneficial agent in the beneficial agent mixture. Forexample, a beneficial agent-polymer mixture having a higherconcentration of polymer would have a slower delivery rate of thebeneficial agent within the lumen. In contrast, a beneficialagent-polymer mixture having a lower concentration of polymer wouldcause a more rapid delivery rate of the beneficial agent. The deliveryrate is also effected by the difference between the LogP value of thehydration inhibitor and the LogP value of the beneficial agent. Forexample, generally the greater the difference between the LogP valuesthe greater the retardation of the beneficial agent's delivery rate ascompared to the beneficial agent without hydration inhibitor.

Examples of additives suitable as hydration inhibitors includeplasticizers, small molecules and oils. Additives are drawn fromcompounds, polymers, and mixtures without restriction. When used with aninterventional device having a polymer coating, an additive is oftencapable of dispersing through the polymer coating and rendering iteffectively more difficult to hydrate as empirically defined as anincrease in swelling time in contact with aqueous solution vs. controlpolymer coating.

Specific non-limiting examples of additives include nitrophenyl octylether, bisethylhexyl sebacate, diisododecylphthalate,N-methylpyrrolidone, linolenic acid, linoleic acid, stearic acid, oleicacid, and combinations thereof.

The hydration inhibitor can be associated with the beneficial agent inany of a variety of conventional techniques. As embodied herein, and aspreviously noted, it is to associate the hydration inhibitor with thebeneficial agent as a mixture of the compounds. The mixture can beaccomplished by a physical combination in a variety of forms, includingsolution, suspension, solid interspersion, vapor phase deposition or anyphysical combination.

An additional aspect of the invention includes the use of a base layerof polymer material to facilitate loading of a beneficial agent on theinterventional component. This aspect of the invention is of particularimportance if the beneficial agent is difficult or unsuitable forloading alone or in combination with a suitable binder or the like.

When a coating is used in the invention, the coating can include anypolymeric material in which the therapeutic agent, i.e., the drug, issubstantially soluble. The purpose of the coating is to serve as acontrolled release vehicle for the therapeutic agent or as a reservoirfor a therapeutic agent to be delivered at the site of a lesion. Thecoating can be polymeric and can further be hydrophilic, hydrophobic,biodegradable, or non-biodegradable. The material for the polymericcoating can be selected from the group consisting of polycarboxylicacids, cellulosic polymers, gelatin, polyvinylpyrrolidone, maleicanhydride polymers, polyamides, polyvinyl alcohols, polyethylene oxides,glycosaminoglycans, polysaccharides, polyesters, polyurethanes,silicones, polyorthoesters, polyanhydrides, polycarbonates,polypropylenes, polylactic acids, polyglycolic acids, polycaprolactones,polyhydroxybutyrate valerates, polyacrylamides, polyethers, and mixturesand copolymers of the foregoing. Coatings prepared from polymericdispersions including polyurethane dispersions (BAYHYDROL, etc.) andacrylic acid latex dispersions can also be used with the therapeuticagents of embodiments of the invention.

Biodegradable polymers that can be used in this invention includepolymers including poly(L-lactic acid), poly(DL-lactic acid),polycaprolactone, poly(hydroxy butyrate), polyglycolide,poly(diaxanone), poly(hydroxy valerate), polyorthoester; copolymersincluding poly (lactide-co-glycolide), polyhydroxy(butyrate-co-valerate), polyglycolide-co-trimethylene carbonate;polyanhydrides; polyphosphoester; polyphosphoester-urethane; polyaminoacids; polycyanoacrylates; biomolecules including fibrin, fibrinogen,cellulose, starch, collagen and hyaluronic acid; and mixtures of theforegoing. Biostable materials that are suitable for use in thisinvention include polymers include polyurethane, silicones, polyesters,polyolefins, polyamides, polycaprolactam, polyimide, polyvinyl chloride,polyvinyl methyl ether, polyvinyl alcohol, acrylic polymers andcopolymers, polyacrylonitrile, polystyrene copolymers of vinyl monomerswith olefins (including styrene acrylonitrile copolymers, ethylenemethyl methacrylate copolymers, ethylene vinyl acetate), polyethers,rayons, cellulosics (including cellulose acetate, cellulose nitrate,cellulose propionate, etc.), parylene and derivatives thereof; andmixtures and copolymers of the foregoing.

A medical devices to which coatings are applied according to theinvention can be pretreated to prepare the surfaces for application ofcoatings. For example, stainless steel stents may be electropolishedprior to coating (e.g., undercoat) application. Useful medical devicescan be formed from NITINOL alloy, TRIPLEX (stainlesssteel/tantalum/stainless steel layer) or cobalt chromium alloy. Thecoatings optionally include a polymeric material, e.g.,phosphorylcholine, polycaprolactone, poly-D,L-lactic acid, poly-L-lacticacid, poly(lactide-co-glycolide), poly(hydroxybutyrate),poly(hydroxybutyrate-co-valerate), polydioxanone, polyorthoester,polyanhydride, poly(glycolic acid), poly(glycolic acid-co-trimethylenecarbonate), polyphosphoester, polyphosphoester urethane, poly(aminoacids), cyanoacrylates, poly(trimethylene carbonate),poly(iminocarbonate), polyalkylene oxalates, polyphosphazenes,polyiminocarbonates, and aliphatic polycarbonates, fibrin, fibrinogen,cellulose, starch, collagen, Parylene® brand poly-para-xylylene(available from SCSCookson Industries, Indianapolis, Ind.), Paryl AST™brand biocompatible dielectric polymer (U.S. Pat. Nos. 5,355,832 and5,447,799, commercially available from AST Products of Billerica,Mass.); polyurethane, polycarbonate urethanes, polyethylene,polyethylene terephthalate, ethylene vinyl acetate, ethylene vinylalcohol, silicone polysiloxanes, substituted polysiloxanes, polyethyleneoxide, polybutylene terephthalate-co-PEG, PCL-co-PEG (i.e.,polycaprolactone co-polyethylene glycol), PLA-co-PEG (i.e., polylacticacid-co-polyethylene glycol), polyacrylates, polyvinyl pyrrolidone,polyacrylamide, thermoplastic elastomers, polyolefin elastomers, EPDMrubbers, polyamide elastomers, biostable plastic, acrylic polymers,nylon, polyesters, epoxies and derivatives or blends thereof (e.g.,PLLA-phosphorylcholine).

In any of the embodiments disclosed herein, a porous or biodegradablemembrane or layer made of biocompatible materials may be coated over thebeneficial agent for sustained release thereof, if desired.Alternatively, a suitable base coating capable of retaining beneficialagent therein can be applied uniformly over the surface of theprosthesis, and then selected portions of the base coating can be loadedwith the beneficial agent in accordance with embodiments of theinvention. A greater amount of beneficial agent can be loaded over aunit surface area intended to have a greater local areal density and alower amount of beneficial agent can be loaded over a unit surface areaintended to have a lower local areal density.

In yet another embodiment of the invention, the beneficial agent may beapplied directly to the surface of the prosthesis. Generally a binder orsimilar component may be used to ensure sufficient adhesion. Forexample, this coating technique may include admixing the beneficialagent with a suitable binder or polymer to form a coating mixture, whichis then coated onto the surface of the prosthesis. The coating mixturewould be prepared in higher or lower concentrations of beneficial agentas desired, and then applied to selected portions of the prosthesisappropriately.

As noted above, the beneficial agent may be applied to theinterventional component in a polymer, include drug/polymer mixture. Theamount of polymer in the mixture is small compared to the amount ofdrug. For example, the polymer can be about 10% of the amount of drug.In these embodiments, the polymer facilitates processing or loading orenhances retention of the drug on the interventional device, but is inan amount that is not effective to substantially inhibit the hydrationof the drug. The presence of the hydration inhibitor of suitable LogP asset forth above has the greater influence on delivery of the drug inthis circumstance.

In accordance with some embodiments of the invention, the first andsecond beneficial agents may correspond to drug-polymer mixtures havingdifferent concentrations of polymer to effect different release rates ofthe particular drug in each beneficial agent. For example, thedrug-polymer mixture having a higher concentration of polymer would havea slower release of the drug within the lumen. In contrast, thedrug-polymer mixture having a lower concentration of polymer would causea more rapid release of the drug. Alternatively, rather than providingdrug-polymer mixtures having different polymer concentrations to providedifferent release rates, it is also possible to dispense beneficialagents within different polymers or other binders, wherein the specificpolymer or binder has different diffusivity or affinity to assuredelivery of the beneficial agents at different rates. Thus, inaccordance with the invention, multiple beneficial agents can bereleased at rates appropriate for their activities and the prosthesis ofthe invention has multiple beneficial agents that elute off theprosthesis at desired rates.

For example, a cationic phosphorylcholine which has a higher affinityfor anionic therapeutic agents can be blended and dispersed as a firstbeneficial agent and lipophilic phosphorylcholine can be blended withlipophilic drugs as the second beneficial agent to effect differentrelease rates respectively.

As discussed in greater detail below, the beneficial agent(s) andhydration inhibitors can be applied to the medical device in one or morecoating layers. For example, alternating layers may be used to controldelivery of multiple beneficial agents. Beneficial agents can be appliedto the medical device alone or in combination with a suitable hydrationinhibitor. Coatings that are suitable for use in this invention include,but are not limited to, any biocompatible polymeric material havingsuitable mechanical properties and in which the beneficial agent(s) issubstantially soluble.

Conventional coating techniques also may be utilized to coat thebeneficial agent onto the surface of the prosthesis such as spraying,dipping or sputtering and still provide the desired effect if performedappropriately. With such techniques, it may be desirable or necessary touse known masking or extraction techniques to control the location andamount in which beneficial agent is loaded.

According to some embodiments of the invention, the beneficial agent maybe loaded directly onto a component (e.g., by pipetting) oralternatively, the beneficial agent is loaded onto a base material layerthat is applied a surface of the component (e.g., dip loading). Forexample and not limitation, a base coating, such as a binder or suitablepolymer, is applied to a selected surface of the interventionalcomponent. When desired, a pattern may be formed on a component surface.Beneficial agent is then applied directly to the pattern of the basematerial. Thus, in accordance with the invention, beneficial agent canbe delivered at rates appropriate for the intended use or application.

For purposes of explanation and illustration, and not limitation,exemplary embodiments of the interventional device in accordance withthe invention are shown in FIGS. 1-7. In accordance with one aspect ofthe invention, as shown in FIG. 1, the interventional device is stent 5,having stent struts 10. In an embodiment the interventional device inthe form of a stent 5 has a base phosphorylchoine coating in which thebeneficial drug is loaded. FIG. 3A shows a cross-sectional view of avessel segment in which was placed a stent 5 coated with a PC polymeronly, and FIG. 3B shows a cross-sectional view of a vessel segment inwhich was placed a stent 5 coated with a polymer plus drug. To furtherillustrate the different embodiments of the invention, a cross-sectionalview of a stent strut 10 of the stent 5 of FIG. 1 is shown in FIGS. 4-7.In one embodiment of the invention, seen in FIG. 4, the stent strut 10is loaded with a layer of beneficial agent 11 associated with ahydration inhibitor 12 as a mixture. As embodied herein, the mixture isloaded on the stent strut 10 thicker on one side for increased dosagewhen desired. In other embodiments not shown, however, the beneficialagent 11 and hydration inhibitor 12 can be loaded evenly throughout orselectively at desired locations on the surface of the interventionalcomponent. In a different embodiment of the invention as shown in FIG.5, the stent strut 10 is loaded with a layer of beneficial agent 11,which is covered by a layer of a second beneficial agent acting as ahydration inhibitor 22. In yet another embodiment of the invention,shown in FIG. 6, the stent strut 10 has a base layer of a polymermaterial 31, preferably phosphorlycholine, wherein the polymer materialis loaded with a beneficial agent 32 associated with a hydrationinhibitor 12 as a mixture. FIG. 7 depicts yet another embodiment of theinvention wherein a stent strut 10 has a base layer of polymer material31 loaded with a beneficial agent 32, and a coating of a secondbeneficial agent acts as a hydration inhibitor 22 to control delivery ofthe first beneficial agent.

Furthermore, in a different embodiment of the invention as seen in thecross sectional view of FIG. 8 a stent strut 10 has layers 11A, 11B and11C of a first beneficial agent alternating with layers 12A and 12B of asecond beneficial agent/hydration inhibitor. According to thisembodiment, first beneficial agent, e.g., estradiol, from layer 11Celutes in an initial burst. Second beneficial agent/hydration inhibitor,e.g., zotarolimus, in layer 12B controls elution of first beneficialagent from layer 11B. Thus, the LogP value of the second beneficialagent/hydration inhibitor is greater than the LogP value of the firstbeneficial agent, in accordance with principles of the invention.Similarly, second beneficial agent/hydration inhibitor in layer 12Acontrols elution of first beneficial agent in layer 11A. Layers 12A and12B enable midterm and late term delivery of first beneficial agentalong with second beneficial agent/hydration inhibitor. Depending on thebeneficial agents selected, layers 11A, 11B, 11C, 12A and 12B mayoptionally contain a polymer carrier or binder or other additive tofacilitate processing or retention of the beneficial agent on theinterventional device.

As those skilled in the art will appreciate, many variations of thisembodiment are possible, depending on the medical condition(s) beingtreated, number and identity of beneficial agents selected, desiredorder of delivery and other factors. For example, layers 11A, 11B and11C need not include the same beneficial agent. Each can include adifferent beneficial agent or two can include the same beneficial agentwith the third including another beneficial agent. Similarly, layers 12Aand 12B need not contain the same beneficial agent. Although not shownhere, even more complicated variations can be achieved by those skilledin the art using the principles disclosed herein. For example, it may bedesirable to achieve a relatively early delivery of estradiol to treatsurface monocytes and a delayed delivery of dexamethasone to treattissue monocytes and macrophages.

In an embodiment of the invention, the hydration inhibitor has a LogPvalue of greater than 4.5 units and the beneficial agent has a LogPvalue less than 3 units. In this manner, the hydration inhibitor acts asa water barrier for the less hydrophobic beneficial agent, therebyreducing the release rate of the beneficial agent. For example and notlimitation, the less hydrophobic beneficial agent can be ABT 620{1-Methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide}, ABT 627,ABT 518{[S-(R*,R*)]-N-[1-(2,2-dimethyl-1,3-dioxol-4-yl)-2-[[4-[4-(trifluoro-methoxy)-phenoxy]phenyl]sulfonyl]ethyl]-N-hydroxyformamide},dexamethasone and the like and the hydration inhibitor can beFenofibrate, Tricor™ or3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)-9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-Hexadecahydro-9,27-dihydroxy-3-[(1R)-2-[(1S,3R,4R)-3-methoxy-4-tetrazol-1-yl)cyclohexyl]-1-methylethyl]-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-23,27-epoxy-3H-pyrido[2,1-c][1,4]oxaazacyclohentriacontine-1,5,11,28,29(4H,6H,31H)-pentone;23,27-Epoxy-3H-pyrido[2,1-c][1,4]oxaazacyclohentriacontine-1,5,11,28,29(4H,6H,31H)-pentone.

The intervention component can include at least one reservoir or cavitytherein. In accordance with another aspect of the invention, one or moreof the reservoirs or cavities is loaded with a more hydrophilic firstbeneficial agent and then a second more hydrophobic beneficial agent canbe loaded onto the first beneficial agent within the cavity or reservoirin a manner as described above.

In another embodiment of the invention, the interventional device caninclude a third beneficial agent. The third beneficial agent can be anyof the beneficial agents disclosed above. In an embodiment the thirdbeneficial agent covers the second beneficial agent, the thirdbeneficial agent having a LogP value less than the second LogP for rapidrelease of the third beneficial agent. In this embodiment the thirdbeneficial agent can be the same as the first, so the beneficial agentis released rapidly upon implantation followed by a controlled releaseof the beneficial agent.

The invention also provides a method for manufacturing a medical devicefor controlled delivery of beneficial agent. This method comprises thesteps of providing an interventional component to be deployed in apatient; loading a beneficial agent on the interventional component fordelivery therefrom, the beneficial agent having a first LogP value; andassociating an effective amount of a hydration inhibitor with thebeneficial agent to control delivery of the beneficial agent from theinterventional component, the hydration inhibitor having a second LogPvalue, the second LogP value being greater than the first LogP value.

A number of methods can be used to load the beneficial agent onto thesurface of the interventional component to provide for a controlledlocal areal density of beneficial agent. For example, the interventionalcomponent can be constructed to include pores or reservoirs which areimpregnated or filled with beneficial agent, alone or in combinationwith a hydration inhibitor. The pores can be sized or spaced apart tocorrespond to or limit the amount of beneficial agent contained thereinin accordance with the desired local areal density pattern along thelength of the interventional device, wherein larger pores or more densespacing would be provided in such portions intended to have a greaterlocal areal density.

According to various embodiments of the invention, the beneficial agentcan be loaded directly onto the interventional component oralternatively, the beneficial agent is loaded onto a base material layerthat is applied to at least a portion of the interventional component.For example and not limitation, a base coating, including a binder orsuitable polymer, is applied to a selected surface of the interventionalcomponent such that a desired pattern is formed on the interventionalcomponent surface. Beneficial agent and hydration inhibitor is thenapplied directly to the pattern of the base material. Generally,“controlled areal density” is understood to mean a known orpredetermined amount of beneficial agent or mixture of beneficial agentand hydration inhibitor, either by weight or volume, over a unit surfacearea of the interventional component. In one aspect of the invention,the desired pattern corresponds to the desired controlled local arealdensity. For example, a greater amount of base material layer is appliedto portions of the interventional device intended to have a greaterlocal areal density of beneficial agent, and a lesser amount of basematerial is applied to portions of the interventional device intended tohave a lower local areal density of beneficial agent. In yet anotherembodiment of the invention, the beneficial agent can be applieddirectly to the surface of the interventional component.

Conventional coating techniques also can be utilized to coat thebeneficial agent onto the surface of the interventional component suchas spraying, dipping or sputtering and still provide the desired effectif performed appropriately. With such techniques, it can be desirable ornecessary to use known masking or extraction techniques to control thelocation and amount in which beneficial agent is loaded. See U.S. patentapplication Ser. No. 09/950,307, filed Sep. 10, 2001; U.S. Pat. Nos.6,329,386 and 6,015,815; and U.S. Patent Provisional Applicationentitled, “Medical Device Having a Hydration Inhibitor,” filed on Mar.10, 2003, each of which is incorporated herein by reference.

In yet another aspect of the invention, the beneficial agent(s)described herein can be applied to an intervention component that hasbeen coated with a polymeric compound. Incorporation of the compound ordrug into the polymeric coating of the interventional component can becarried out by dipping the polymer-coated interventional component intoa solution containing the compound or drug for a sufficient period oftime (such as, for example, five minutes) and then drying the coatedinterventional component, preferably by means of air drying for asufficient period of time (such as, for example, 30 minutes). Thepolymer-coated interventional component containing the compound or drugcan then be delivered to the coronary vessel by deployment from aballoon catheter, for example.

In another embodiment, the beneficial agent and hydration inhibitor is“printed” onto the surface of the interventional component by afluid-dispenser having a dispensing element capable of dispensingbeneficial agent in discrete droplets, wherein each droplet has acontrolled trajectory. In particular, the beneficial agent or mixture isselectively dispensed from the dispensing element to a predeterminedportion of the interventional component in a raster format along adispensing path. Advantageously, fluid-jetting technology can be used todeposit materials, such as beneficial agents and hydration inhibitors,in controlled volumes onto a substrate at a controlled location. SeeU.S. Provisional Patent Application Nos. 60/424,575; 60/424,577;60/424,607; 60/424,574; and 60/424,576, all filed Nov. 7, 2002, each isincorporated by reference herein.

Further in accordance with the invention, the first beneficial agentloaded onto the interventional component has a first local areal densityand the second beneficial agent loaded onto the interventional componenthas a second local areal density. As used herein, “areal density” refersto the amount of beneficial agent per unit surface area of a selectedportion of the interventional component. “Local areal density” refers tothe dosage of beneficial agent per local surface area of theinterventional component. The local areal density of the firstbeneficial agent and the local areal density of the second beneficialagent can be uniform across each respective portion to define steppedchanges in local area density or can be varied across a selected portionof the interventional component to define gradients of local areadensity. Accordingly, a medical device is provided having aninterventional component that is at least partially loaded withbeneficial agent having a local areal density that is varied along aselected portion of the body of the interventional component.

In accordance with the invention, the local areal density can be variedby varying the relative rate in which beneficial agent is loaded to aselected location along the interventional component. To this end, thefrequency in which the droplets of beneficial agent are applied along aunit length of the dispensing path to the interventional component isvaried. Alternatively, the relative rate of loading beneficial agent canbe varied by varying the relative movement between the dispensingelement and the interventional component. Another alternative forvarying the relative rate of loading beneficial agent is to vary theamount of beneficial agent per droplet dispensed from the dispensingelement. Other alternatives for varying the local areal density ofbeneficial agent loaded onto the interventional component include mixingthe beneficial agent with a binder and varying the ratio of beneficialagent to binder. Alternatively, the amount of the mixture of beneficialagent and binder that is applied to the interventional component can bevaried to achieve a varied local areal density of beneficial agent.However, other methods of varying the local areal density of beneficialagent known in the art can be used.

In accordance with another embodiment of the invention, the firstsurface of the interventional component is defined by a plurality ofinterconnecting structural members. Accordingly, the first surface caninclude a first selected set of structural members, e.g., a connectormember, and the second surface can include a second selected set of thestructural members, e.g., a ring-shaped element extending around thecircumference of the interventional component.

Another feature of the invention includes applying a layer of basematerial on a selected portion of the interventional component describedabove. The beneficial agent or mixture with hydration inhibitor isloaded onto the base material layer according to the methods describedabove. The base material layer can define a pattern for loading thebeneficial agent onto the interventional component.

The invention will be further understood by the examples set forthbelow, which are provided for purpose of illustration and notlimitation.

EXAMPLES Example 1 Elution Experiments of Beneficial Agents

I. Coating the Coupon with PC1036

Prior to any experimentation, coated stainless steel coupons wereprepared. These coupons were 316L electropolished stainless steel discs(10 mm diameter). This size was chosen because the surface area of oneside of the coupon is similar to the surface area of a 15-mm open cellBiodivYsio stent. The coupon was prepared by scratching a mark on oneside of the coupon, to indicate the side of the coupon that will not becoated, and then cleaned. The cleaning was a two-step process in whichthe coupons are sonicated for 3 minutes in dichloromethylene and 3minutes in ethanol. The coupons were allowed to dry at room temperature.One side of the coupon was coated using a filtered 20-mg/mL solution ofphosphoryl choline polymer PC1036 (product of Biocompatibles Ltd.,Farnham, Surrey, UK) in ethanol. Twenty μL PC solution was placed ontothe coupon using a gas tight glass syringe, ensuring that the entiresurface was coated but not spilling over the sides of the coupon. Thecoupons were initially air dried and then cured at 70° C. for 16 hours.They were then sent for gamma irradiation at <25 KGy. The resulting PCcoating thickness was close to that of the stent and thick enough toaccommodate the desired loaded drug dose, as graphically represented inFIG. 9A-B. FIG. 9A-B is a top and side view of a coated stainless steelcoupon 30, having a PC-coating 20 on a electropolished stainless steeldisc.

II. Loading the Coupon with Drugs of Interest

In these experiments, beneficial agents were loaded onto coupons andelution profiles examined. In general, the procedure is as follows.Twelve PC-coated coupons were loaded with each drug. The solutions ofthe drugs were usually 5.0 mg/mL in 100% ethanol and were filtered witha 0.45 μm filter prior to use.

The coupons were weighed before loading with the drug solution. To load100 μg of drug, 20 μL of solution was placed (e.g., pipetted) on thecenter of the PC coated side of the coupon. The coupon was placed in avial for 30 minutes with the lid closed to allow the drug to penetratethe coating. The lid was removed and the coupon was allowed to dry foran additional 90 minutes. To ensure that the coupon was completely dry,the coupon was weighed, and after 15 minutes the coupon was weighed athird time. When two weightings of the coupon were the same, the couponwas considered dry. The loaded, dry coupons were stored in arefrigerator protected from light.

III. Extracting Drugs from the Coupon

For each drug, six coupons were used to evaluate the total amount ofdrug loaded by the above procedure. The coupons were immersed in 5 mL of50% ethanol, 50% water solution and sonicated for 1 hour. Theconcentration of the drug in the extraction solution was analyzed byHPLC.

At the end of the elution experiments discussed below, the coupons wereremoved from the elution media and immersed in 5 mL of 50% ethanol, 50%water solution and sonicated for 1 hour. The concentration of the drugin these vials indicated the amount of the drug remaining in the couponsat the end of the elution experiments.

IV. Elution Process

Six coated coupons of each drug were used for the elution experiments.The coupons were individually placed, coating side up, in small metalcups to hold the coupon and to allow movement to a new vial at each timepoint. The coupons were usually placed in a vial containing 10 mL of pH7.4 phosphate buffered saline. The vials were stored in an orbitalshaker, with horizontal shaking of 100 rpm, at 37° C. for at least 30minutes before insertion of a coupon to allow the solution toequilibrate at the desired temperature. At least nine different timepoints were observed as shown in Table 2. After the desired time hadlapsed, the coupon holder was lifted and allowed to drain. It was thenplaced into a pre-warmed vial corresponding to the next time point. Thisprocedure continued until the predetermined time had elapsed. At thatpoint, the coupons went through a drug extraction step as outlinedearlier. The amount of drug in the elution samples was determined byHPLC.

To illustrate the effect of a relatively less hydrophilic beneficialagent/hydration inhibitor on a relatively more hydrophilic beneficialagent (i.e., a combination drugs) several different loading procedureswere investigated. In particular for zotarolimus and dexamethasonecombination the following were investigated.

TABLE 2 One-Day Elution Study Time and Sample Size Elution SampleElution Time Volume Number (Days) (Hours) (mL) 1 0.003 0.08 (5 min)  102 0.010 0.25 (15 min) 10 3 0.021 0.50 (30 min) 10 4 0.042 1 10 5 0.083 210 6 0.125 3 10 7 0.167 4 10 8 0.208 5 10 9 0.250 6 10

FIGS. 10, 11, 12, 13 and 14 illustrate the effect of a hydrationinhibitor according to the invention on the elution of a relatively morehydrophilic beneficial agent. In FIGS. 10-13, the drugs were applied tocoupons; in FIG. 14, stents were coated.

In FIG. 10, the six-hour elution profile shown is where the beneficialagent is fenofibrate and the hydration inhibitor is zotarolimus. Elutionwas carried out as described above. Curve A is the elution profile ofzotarolimus alone. Curves B and C are the profiles for fenofibrate, incombination with zotarolimus and alone, respectively. Curve B shows thatonly about 7% of the fenofibrate was released from the coupon after 6hours. As can be seen by comparing Curves B and C, the release offenofibrate was significantly reduced by the presence of zotarolimus.

FIG. 11 illustrates the six-hour elution profile of beneficial agentABT-627 (atrasentan) in the presence of hydration inhibitor zotarolimus.Curves A and C are the elution profiles of ABT-627, in the presence ofzotarolimus and alone, respectively. Curve B shows the elution ofzotarolimus under the same conditions. Comparing Curves A and C, it isseen that the elution rate of relatively more hydrophilic ABT-627 isreduced in the presence of relatively less hydrophilic zotarolimus.After six hours, much less than 10% of ABT-627 was released in thepresence of zotarolimus (Curve C), compared to 50% in the absence ofzotarolimus (Curve A).

FIG. 12 illustrates the six-hour elution profile of beneficial agentdipyridamole in the presence of hydration inhibitor zotarolimus. CurvesA and B are the elution profiles of dipyridamole, in the presence ofzotarolimus and alone, respectively. Curve C shows the elution profileof ABT 578 under the same conditions. As can be seen by comparing CurvesA and B, the amount of dipyridamole released from the coupons coatedwith zotarolimus and dipyridamole is only about 52% after six hours,compared to nearly 90% in the absence of zotarolimus.

FIG. 13 illustrates the six-hour elution profiles of beneficial agentdexamethasone in the presence of hydration inhibitor zotarolimus. CurvesA and B are the elution profiles of dexamethasone, alone and in thepresence of zotarolimus, respectively. Curves C and D (superimposed) arethe elution profiles for zotarolimus, alone and in the presence ofdexamethasone, respectively, under the same conditions. As can be seenby comparing Curves A and B, the amount of dexamethasone remaining onthe coupon containing dexamethasone and zotarolimus was nearly 70%compared to only 25% on the coupon on which no zotarolimus was present.

FIG. 14 illustrates the six-hour elution profile of beneficial agentdexamethasone in the presence of hydration inhibitor zotarolimus on aPC-coated stent. Loading was accomplished by dip loading, that I,s astent was dipped into a solution containing either one or both drugs andthen permitted to dry. Curves A and B are the elution profiles fordexamethasone in the presence of zotarolimus and alone, respectively.Curves C and D are the elution profiles for zotarolimus in the presenceof dexamethasone and alone, respectively. As can be seen by comparingCurves A and B, after 24 hours, almost no dexamethasone was releasedfrom the stent containing zotarolimus and dexamethasone, though about40% of the dexamethasone was released from the stent having nozotarolimus present in the coating.

Example 2 Elution Experiments of Dexamethasone from Stents

I. Coating the Stents with PC1036

Prior to any experimentation, coated stents were prepared. These were3.0 mm×15 mm 316L electropolished stainless steel stents. Each stent wasspray coated using a filtered 20-mg/mL solution of phosphoryl cholinepolymer PC1036 (product of Biocompatibles Ltd., Farnham, Surrey, UK) inethanol. The stents were initially air dried and then cured at 70° C.for 16 hours. They were then sent for gamma irradiation at <25 KGy.

II. Loading the Stents with Drugs of Interest

In these experiments, beneficial agents were loaded onto stents andelution profiles examined. In general, the procedure was as follows.Multiple PC-coated stents were loaded with each drug combinationsolution. The solutions of the drugs were usually in the range of 2-20mg/mL of zotarolimus and 10.0 mg/mL dexamethasone in 100% ethanol, with˜10% PC1036 added to the solution to enhance film formation.

The stents were weighed before loading with the drug solution. To loadapproximately 10 μg/mL of each drug, a solution with equal amounts ofzotarolimus and dexamethasone was sprayed onto the stent in a controlledfashion. The stent was allowed to dry before the stents were re-weightedto determine total drug load. The loaded, dry stents were stored in arefrigerator and were protected from light.

III. Extracting Drugs from the Stent

For each drug, 3 stents were used to evaluate the total amount of drugloaded by the above procedure. The stents were immersed in 6 mL of 50%ethanol, 50% water solution and sonicated for 20 minutes. Theconcentration of the drug in the extraction solution was analyzed byHPLC.

At the end of the accelerated elution experiments discussed below, thestents were removed from the dissolution media and immersed in 5 mL of50% ethanol, 50% water solution and sonicated for 20 minutes. Theconcentration of the drug in these vials indicated the amount of thedrug remaining on the stents at the end of the accelerated elutionexperiments. In this way, drug extraction was measured.

IV. Accelerated Elution Process

An HPLC method was developed for the determination of the amount ofzotarolimus and dexamethasone eluted from phosphorylcholine (PC) coatedmetal stents (described above) in dissolution studies using an aqueoussolution of polyethylene glycol 660 buffered at pH 4 as the dissolutionmedium. The method is used to determine the amount of drug that haseluted from the stent into the dissolution medium at 37° C. at selectedtime points, typically in a 24-hour period. This rapid, in vitro elutiontest is intended for use as a quality check on the manufacturing processand a fast reliable research tool for understanding the factorscontrolling elution of drugs from stents.

Two coated stents of each drug combination ratio were used for theaccelerated elution experiments. The stents were individually droppedinto the 1 liter containers of the dissolution bath apparatus containing500 mL of dissolution medium at 37° C. The dissolution bath stirringpaddles operated at 50 rpm. An autosampler was programmed to pullsamples at multiple time points (Table 4). This procedure continueduntil the predetermined time had elapsed. At that point, the stent wentthrough a drug extraction step as outlined earlier. The amount of drugin the elution samples was determined by HPLC.

To illustrate the effect of a relatively less hydrophilic beneficialagent/hydration inhibitor on a relatively more hydrophilic beneficialagent (i.e., a combination drugs) several different loading ratios wereinvestigated. In particular, for zotarolimus/dexamethasone(zotarolimus/dex) combinations, the following were investigated at theratios and loading solution concentrations set forth in Table 3, below.

TABLE 3 Loading Solution Ratios Concen- tration Dexa- Concen- SolutionRatio metha- tration Concentration Number of Zotarolimus:Dex soneZotarolimus PC1036 Stents 1:2 10 mg/ml 20 mg/ml 3 mg/ml 6 1:1 10 mg/ml10 mg/ml 2 mg/ml 6 4:3 10 mg/ml 7.5 mg/ml 1.75 mg/ml 6 2:1 10 mg/ml 5mg/ml 1.5 mg/ml 6 5:1 10 mg/ml 2 mg/ml 1.2 mg/ml 6

TABLE 4 One-Day Accelerated Elution Study Time Points Data Time PointsPoint (minutes) 1 5 2 10 3 15 4 30 5 45 6 60 7 90 8 120 9 150 10 180 11240 12 300 13 360 14 420 15 480 16 720 17 960 18 1200 19 1440

FIG. 15 illustrates the effect of a hydration inhibitor according to theinvention on the elution of a relatively more hydrophilic beneficialagent from, for example, a stent.

In particular, FIG. 15 illustrates accelerated elution profiles(generated for example, by the technique described above) of beneficialagent dexamethasone in the presence of hydration inhibitor zotarolimusat different ratios. Curves A and B are the accelerated elution profilesof dexamethasone. As can be seen from the table in the plot, the amountof dexamethasone is higher than zotarolimus. Curves C and D show theaccelerated elution profiles for dexamethasone. In these curves, theratio of zotarolimus-to-dexamethasone increases to 1:1 and 2:1. As canbe seen by comparing Curves A through D, dexamethasone elution becomesincreasingly slow with increasing zotarolimus concentration. Thus, theamount of dexamethasone remaining on a zotarolimus/dexamethasone coatedstent increases as the ratio of zotarolimus-to-dexamethasone increases.

Thus zotarolimus acts as an elution inhibitor for the more hydrophilicdexamethasone, further supporting the conclusion that relatively lesshydrophilic beneficial agents can act as hydration inhibitors ofrelatively more hydrophilic agents.

Example 3 Protection of Dexamethasone from Degradation by the Presenceof Zotarolimus

I Dexamethasone/Zotarolimus/PC Coated Stents

In these experiments, beneficial agents were loaded onto stents and thestability of the two drugs was examined. In general, the procedure wasas follows. Multiple PC-coated stents were loaded with each drugcombination from solution. The solutions of the drugs were usually inthe range of 2-20 mg/mL of zotarolimus and 10.0 mg/mL dexamethasone in100% ethanol, with ˜10% PC1036 added to the solution to enhance filmformation.

The stents were weighed before loading with the drug solution. To loadapproximately 10 μg/mL of each drug, a solution with equal amounts ofzotarolimus and dexamethasone was sprayed onto the stent in a controlledfashion. The stent was allowed to dry before the stents were re-weighedto determine total drug load. The loaded, dry stents were stored in arefrigerator and were protected from light.

II. ETO Sterilization of Stents

After drug loading, stents were crimped onto catheter balloons andpackaged into medical product Tyvek pouches for ETO (ethylene oxide)sterilization. The ETO sterilization process is standard in the medicaldevice industry to ensure product safety. The ETO process was performedin a high humidity, elevated temperature environment to ensure microbeand spore kill.

III. Extracting Drugs from the Stent

For each drug, multiple stents were used to evaluate the purity andstability of the drug loaded by the above procedure. The stents wereimmersed in 6 mL of 50% ethanol, 50% water solution and sonicated for 20minutes. The concentration and the presence of degradant-relatedimpurities of the drug in the extraction solution were analyzed by HPLC.

FIG. 16 shows the overlay of a chromatogram of a stent loaded with onlydexamethasone and a chromatogram of a stent loaded with bothdexamethasone and zotarolimus at a 1-to-1 ratio. As can be seen in thefigure, dexamethasone in the dexamethasone-only coating degraded in theETO sterilization environment with the production of at least threeimpurity peaks at 8.3, 11.3, and 21.8 minutes. In contrast,dexamethasone that was loaded in combination with zotarolimus in thissame high humidity environment did not degrade. The impurity peaks seenin the dexamethasone-only coated stents were not present, nor were anyimpurity peaks evident in the chromatogram.

This figure thus demonstrates that zotarolimus acts a hydrationinhibitor for the more hydrophilic dexamethasone, and that thisinhibition has the effect of stabilizing the more hydrophilic drugdexamethasone in the presence of the less hydrophilic drug zotarolimus.

Preparation of Compound of the Invention

The compounds and processes of embodiments of the invention will bebetter understood in connection with the following synthetic schemeswhich illustrate the methods by which the compounds of the invention maybe prepared.

The compounds of this invention may be prepared by a variety ofsynthetic routes. A representative procedure is shown in Scheme 1.

As shown in Scheme 1, conversion of the C-42 hydroxyl of rapamycin to atrifluoromethanesulfonate or fluorosulfonate leaving group provided A.Displacement of the leaving group with tetrazole in the presence of ahindered, non-nucleophilic base, such as 2,6-lutidine, or, preferably,diisopropylethyl amine provided epimers B and C, which were separatedand purified by flash column chromatography.

Synthetic Methods

The foregoing may be better understood by reference to the followingexamples which illustrate the methods by which the compounds of theinvention may be prepared and are not intended to limit the scope of theinvention as defined in the appended claims.

Example 1 42-Epi-(tetrazolyl)-rapamycin (less polar isomer) Example 1A

A solution of rapamycin (100 mg, 0.11 mmol) in dichloromethane (0.6 mL)at −78° C. under a nitrogen atmosphere was treated sequentially with2,6-lutidine (53 uL, 0.46 mmol, 4.3 eq.) and trifluoromethanesulfonicanhydride (37 uL, 0.22 mmol), and stirred thereafter for 15 minutes,warmed to room temperature and eluted through a pad of silica gel (6 mL)with diethyl ether. Fractions containing the triflate were pooled andconcentrated to provide the designated compound as an amber foam.

Example 1B 42-Epi-(tetrazolyl)-rapamycin (less polar isomer)

A solution of Example 1A in isopropyl acetate (0.3 mL) was treatedsequentially with diisopropylethylamine (87 L, 0.5 mmol) and1H-tetrazole (35 mg, 0.5 mmol), and thereafter stirred for 18 hours.This mixture was partitioned between water (10 mL) and ether (10 mL).The organics were washed with brine (10 mL) and dried (Na₂SO₄).Concentration of the organics provided a sticky yellow solid which waspurified by chromatography on silica gel (3.5 g, 70-230 mesh) elutingwith hexane (10 mL), hexane:ether (4:1(10 mL), 3:1(10 mL), 2:1(10 mL),1:1(10 mL)), ether (30 mL), hexane:acetone (1:1(30 mL)). One of theisomers was collected in the ether fractions.

MS (ESI) m/e 966 (M)⁻;

Example 2 42-Epi-(tetrazolyl)-rapamycin (more polar isomer) Example 2A42-Epi-(tetrazolyl)-rapamycin (more polar isomer)

Collection of the slower moving band from the chromatography columnusing the hexane:acetone (1:1) mobile phase in Example 1B provided thedesignated compound.

MS (ESI) m/e 966 (M)⁻.

In vitro Assay of Biological Activity

The immunosuppressant activity of the compounds of the present inventionwas compared to rapamycin and two rapamycin analogs:40-epi-N-[2′-pyridone]-rapamycin and 40-epi-N-[4′-pyridone]-rapamycin.The activity was determined using the human mixed lymphocyte reaction(MLR) assay described by Kino, T. et al. in Transplantation Proceedings,XIX(5):36-39, Suppl. 6 (1987). The results of the assay demonstrate thatthe compounds of the invention are effective immunomodulators atnanomolar concentrations, as shown in Table 1.

TABLE 1 Human MLR Example IC₅₀ ± S.E.M. (nM) Rapamycin 0.91 ± 0.362-pyridone 12.39 ± 5.3  4-pyridone 0.43 ± 0.20 Example 1 1.70 ± 0.48Example 2 0.66 ± 0.19

The pharmacokinetic behaviors of Example 1 and Example 2 werecharacterized following a single 2.5 mg/kg intravenous dose incynomolgus monkey (n=3 per group). Each compound was prepared as 2.5mg/mL solution in a 20% ethanol:30% propylene glycol:2% cremophor EL:48%dextrose 5% in water vehicle. The 1 mL/kg intravenous dose wasadministered as a slow bolus (1-2 minutes) in a saphenous vein of themonkeys. Blood samples were obtained from a femoral artery or vein ofeach animal prior to dosing and 0.1 (IV only), 0.25, 0.5, 1, 1.5, 2, 4,6, 9, 12, 24, and 30 hours after dosing. The EDTA preserved samples werethoroughly mixed and extracted for subsequent analysis.

An aliquot of blood (1.0 mL) was hemolyzed with 20% methanol in water(0.5 ml) containing an internal standard. The hemolyzed samples wereextracted with a mixture of ethyl acetate and hexane (1:1 (v/v), 6.0mL). The organic layer was evaporated to dryness with a stream ofnitrogen at room temperature. Samples were reconstituted in methanol:water (1:1, 150 μL). The title compounds (50 μL injection) wereseparated from contaminants using reverse phase HPLC with UV detection.Samples were kept cool (4° C.) through the run. All samples from eachstudy were analyzed as a single batch on the HPLC.

Area under the curve (AUC) measurements of Example 1, Example 2 and theinternal standard were determined using the Sciex MacQuan™ software.Calibration curves were derived from peak area ratio (parentdrug/internal standard) of the spiked blood standards using leastsquares linear regression of the ratio versus the theoreticalconcentration. The methods were linear for both compounds over the rangeof the standard curve (correlation>0.99) with an estimated quantitationlimit of 0.1 ng/mL. The maximum blood concentration (C_(MAX)) and thetime to reach the maximum blood concentration (T_(MAX)) were readdirectly from the observed blood concentration-time data. The bloodconcentration data were submitted to multi-exponential curve fittingusing CSTRIP to obtain estimates of pharmacokinetic parameters. Theestimated parameters were further defined using NONLIN84. The area underthe blood concentration-time curve from 0 to t hours (last measurableblood concentration time point) after dosing (AUC_(0-t)) was calculatedusing the linear trapeziodal rule for the blood-time profiles. Theresidual area extrapolated to infinity, determined as the final measuredblood concentration (C_(t)) divided by the terminal elimination rateconstant (β), and added to AUC_(0-t) to produce the total area under thecurve (AUC_(0-t)).

As shown in FIG. 1 and Table 2, both Example 1 and Example 2 had asurprisingly substantially shorter terminal elimination half-life(t_(1/2)) when compared to rapamycin. Thus, only the compounds of theinvention provide both sufficient efficacy (Table 1) and a shorterterminal half-life (Table 2).

TABLE 2 AUC t_(1/2) Compound ng · hr/mL (hours) Rapamycin 6.87 16.72-pyridone 2.55 2.8 4-pyridone 5.59 13.3 Example 1 2.35 5.0 Example 22.38 6.9

While the invention has been described, disclosed, illustrated and shownin various terms of certain embodiments or modifications which it haspresumed in practice, the scope of the invention is not intended to be,nor should it be deemed to be, limited thereby and such othermodifications or embodiments as may be suggested by the teachings hereinare particularly reserved especially as they fall within the breadth andscope of the claims here appended.

1. A system for delivering a lipophilic agent to a desired area outsidea body lumen in order to treat a disease manifesting itself in the bodylumen or in organs connected to the body lumen, or to maintain patencyof the body lumen, comprising: a medical device; a first lipophilicagent capable of penetrating the body lumen wherein the transfercoefficient of said first lipophilic agent is by an amount of at least5,000 (μg/mL)⁻¹, wherein said first lipophilic agent compriseszotarolimus having one of the following structures:

 wherein said first lipophilic agent/medical device is placed adjacentto said body lumen; and wherein a therapeutically effective amount ofsaid first lipophilic agent is delivered via the medical device to adesired area outside the body lumen where the medical device is placedwithin a subject.
 2. The system according to claim 1, further comprisingat least one pharmaceutically acceptable carrier or excipient, whereinsaid medical device is connected to said pharmaceutically acceptablecarrier or excipient.
 3. The system according to claim 2, wherein saidpharmaceutically acceptable carrier or excipient is a polymer.
 4. Thesystem according to claim 2, wherein said pharmaceutically acceptablecarrier or excipient is an agent.
 5. The system according to claim 1,wherein said body lumen comprises at least one of a vessel wall, acoronary artery, esophageal lumen, and a urethra.
 6. The systemaccording to claim 5, wherein said first lipophilic agent/medical deviceis placed adjacent to said body, wherein a therapeutically effectiveamount of said first lipophilic agent is delivered into said coronaryarteries and diffused into the pericardial sac in said drug deliverysystem.
 7. The system according to claim 6, wherein said system providessubstantially uniform drug delivery of said lipophilic agent to themyocardium.
 8. The system according to claim 6, wherein said system isuseful for the treatment of vascular diseases in a subject.
 9. Thesystem according to claim 3, wherein said delivery mechanism of saidfirst lipophilic agent includes polymer hydration followed bydissolution of said first lipophilic agent, and wherein said firstlipophilic agent is thereafter delivered into said body lumen.
 10. Thesystem according to claim 3, wherein said delivery mechanism of saidfirst lipophilic agent includes a lipophilic agent/polymer matrix whichcontrols the elution rate of said first lipophilic agent to said bodylumen.
 11. The system according to claim 1, further comprises at leastone second lipophilic agent.
 12. The system according to claim 1,further comprises at least one lipophilic prodrug.
 13. The systemaccording to claim 1, further comprises at least one lipophilicpenetration enhancer.
 14. The system according to claim 13, wherein saidlipophilic penetration enhancer is a pharmaceutical agent.
 15. Thesystem according to claim 11, wherein the concentration of said secondlipophilic agent in combination with said first lipophilic agent is atherapeutically effective amount.
 16. The system according to claim 1,further comprises at least one beneficial agent selected from the groupconsisting of antithrombotics, anticoagulents, antiplatelet agents,antiulcer/antireflux agents, antinauseants/antiemetics and thrombolyticagents.
 17. The system according to claim 1, wherein the dosage deliveryof said first lipophilic agent into said body lumen ranges from about 15μg/g to about 150 μg/g over a period of up to 5 days.
 18. The systemaccording to claim 1, wherein the dosage delivery of said firstlipophilic agent into said body lumen ranges from about 15 μg/g to about80 μg/g over a period from about 5 days to about 15 days.
 19. The systemaccording to claim 1, wherein the dosage delivery of said firstlipophilic agent into said body lumen ranges from about 5 μg/g to about60 μg/g over a period from 15 days to about 28 days.
 20. The systemaccording to claim 1, wherein said first lipophilic agent reachestherapeutically significant concentrations in targeted areas in saidsubject comprising at least one of the distal myocardium, the unstentedmyocardium, in said subjacent myocardium, in unstented and distalcoronary arteries, and maintains those concentrations throughout a 28day period.
 21. The system according to claim 1, wherein said medicaldevice is permanently or temporarily implanted into a subject.
 22. Thesystem according to claim 1, wherein said first lipophilic agent is inamorphous form.
 23. The system according to claim 1, further comprises abeneficial agent including at least one of antithrombotics,anticoagulants, antiplatelets agents, anti-lipid agents, thrombolytics,antiproliferatives, antiinflammatories, agents that inhibit hyperplasia,smooth muscle cell inhibitors antibiotics, growth factor inhibitors,cell adhesion inhibitors, cell adhesion promoters, antimitotics,antifibrins, antioxidants, antineoplastics, agents that promoteendothelial cell recovery, matrix metalloproteinase inhibitors,antimetabolites, antiallergic substances, viral vectors, nucleic acids,monoclonal antibodies, inhibitors of tyrosine kinase, antisensecompounds, oligionucleotides, cell permeation enhancers, andanycombinations thereof.
 24. The system according to claim 1, furthercomprises a beneficial agent including at least one of hypoglycemicagents, hypolipidemic agents, proteins, nucleic acids, agents useful forerythropoiesis stimulation, angiogenesis agents, antiulcer/antirefluxagents, and antinauseants/antiemetics, PPAR-alpha agonists, and anycombinations thereof.
 25. The system according to claim 1, furthercomprises a beneficial agent including at least one of sodium heparin,LMW heparins, heparoids, hirudin, argatroban, forskolin, vapriprost,prostacyclin and prostacylin analogues, dextran,D-phe-pro-arg-chloromethylketone (synthetic antithrombin), glycoproteinIiba/Iia (platelet membrane receptor antagonist antibody), recombinanthirudin, thrombin inhibitors, indomethacin, phenyl salicylate,β-estradiol, vinblastine, ABT-627 (astrasentan), testosterone,progesterone, paclitaxel, methotrexate, fotemusine, RPR-101511A,cyclosporine A, vincristine, carvediol, vindesine, dipyridamole,methotrexate, folic acid, thrombospondin mimetics, estradiol,dexamethasone, metrizamide, iopamidol, iohexol, iopromide, iobitridol,iomeprol, iopentol, ioversol, ioxilan, iodixanol, iotrolan and anycombinations thereof.
 26. The system according to claim 1, wherein saidmedical device is an endovascular medical device.
 27. The systemaccording to claim 1, wherein said medical device includes intracoronarymedical devices selected from the group consisting of stents, drugdelivery catheters, grafts, and drug delivery balloons utilized insubjects' vasculature.
 28. The system according to claim 1, wherein saidmedical device includes a stent selected from the group consisting ofperipheral stents, peripheral coronary stents, degradable coronarystents, non-degradable coronary stents, self-expanding stents,balloon-expanded stents, and esophageal stents.
 29. The system accordingto claim 1, wherein said medical device is selected from the groupconsisting of arterio-venous grafts, by-pass grafts, penile implants,vascular implants and grafts, intravenous catheters, small diametergrafts, artificial lung catheters, electrophysiology catheters, bonepins, suture anchors, blood pressure and stent graft catheters, breastimplants, benign prostatic hyperplasia and prostate cancer implants,bone repair/augmentation devices, breast implants, orthopedic jointimplants, dental implants, implanted drug infusion tubes, oncologicalimplants, pain management implants, neurological catheters, centralvenous access catheters, catheter cuff, vascular access catheters,urological catheters/implants, atherectomy catheters, clot extractioncatheters, PTA catheters, PTCA catheters, stylets (vascular andnon-vascular), drug infusion catheters, angiographic catheters,hemodialysis catheters, neurovascular balloon catheters, thoracic cavitysuction drainage catheters, electrophysiology catheters, stroke therapycatheters, abscess drainage catheters, biliary drainage products,dialysis catheters, central venous access catheters, and parentalfeeding catheters.
 30. The system according to claim 1, wherein saidmedical device is selected from the group consisting of pacemakers,vascular grafts, sphincter devices, urethral devices, bladder devices,renal devices, gastroenteral and anastomotic devices, vertebral disks,hemostatic barriers, clamps surgicalstaples/sutures/screws/plates/wires/clips, glucose sensors, bloodoxygenator tubing, blood oxygenator membranes, blood bags, birthcontrol/IUDs and associated pregnancy control devices, cartilage repairdevices, orthopedic fracture repairs, tissue adhesives, tissue sealants,tissue scaffolds, CSF shunts, dental fracture repair devices,intravitreal drug delivery devices, nerve regeneration conduits,electrostimulation leads, spinal/orthopedic repair devices, wounddressings, embolic protection filters, abdominal aortic aneurysm graftsand devices, neuro aneurysm treatment coils, hemodialysis devices,uterine bleeding patches, anastomotic closures, in vitro diagnostics,aneurysm exclusion devices, neuropatches, vena cava filters, urinarydilators, endoscopic surgical and wound drainings, surgical tissueextractors, transition sheaths and dialators, coronary and peripheralguidewires, circulatory support systems, tympanostomy vent tubes,cerebro-spinal fluid shunts, defibrillator leads, percutaneous closuredevices, drainage tubes bronchial tubes, vascular coils, vascularprotection devices, vascular intervention devices, including vscularfilters and distal supoort devices and emboli filter/entrapment aids, AVaccess grafts, surgical tampons, drug delivery capsule and cardiacvalves.
 31. The system according to claim 1, wherein said medical deviceis selected from the group consisting of atrial septal defect closures,electro-stimulation leads for cardiac rhythm management, tissue andmechanical prosthetic heart valves and rings, arterial-venous shunts,valve annuloplasty devices, mitral valve repair devices, left ventricleassist devices, left atrial appendage filters, cardiac sensors,pacemaker electrodes and leads.
 32. The system according to claim 1,wherein said lipophilic agent is continuously delivered to theepicardium and/or pericardial sac.
 33. The system according to claim 1,wherein said lipophilic agent comprises zotarolimus having bothstructures of claim 1.